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Pain (PDQ®): Supportive care - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

Pain

Overview

The International Association for the Study of Pain defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Cancer pain can be managed effectively through relatively simple means in up to 90% of the eight million Americans who have cancer or a history of cancer. Unfortunately, pain associated with cancer is frequently undertreated.[1]

The highest prevalence of severe pain occurs in adult patients with advanced cancer. Chronic pain is an issue in cancer patients, with up to 33% continuing to have pain after curative therapy. During active cancer treatment and in advanced disease states, tumors cause most pain. However, survivors are affected more by pain related to modalities such as surgery, chemotherapy, or radiation therapy than by cancer-related pain. One summary provides an excellent review of troublesome symptoms in cancer survivors, including pain.[2][Level of evidence: IV]

Although cancer pain or associated symptoms often cannot be entirely eliminated, appropriate use of available therapies can effectively relieve pain in most patients. Pain management improves the patient's quality of life throughout all stages of the disease. Patients with advanced cancer experience multiple concurrent symptoms with pain; therefore, optimal pain management necessitates a systematic symptom assessment and appropriate management for optimal quality of life.[3] Despite the wide range of available pain management therapies, data are insufficient to guide their use in children, adolescents, older adults, and special populations.[4]

State and local laws often restrict the medical use of opioids to relieve cancer pain, and third-party payers may not reimburse for noninvasive pain-control treatments. Thus, clinicians should work with regulators, state cancer pain initiatives, or other groups to eliminate these health care system barriers to effective pain management. (These and other barriers to effective pain management are listed below.) Changes in health care delivery may create additional disincentives for clinicians to practice effective pain management.

The U.S. Food and Drug Administration Amendments Act of 2007 requires manufacturers to provide risk evaluation and mitigation strategies (REMS) for selected drugs to ensure that benefits outweigh risks. A major component of REMS requires prescribers to obtain training so that these drugs can be safely used.

The most appropriate treatment may not be reimbursed or may be too costly for patients and families.[6]

Restrictive regulation of controlled substances.

Problems of availability of treatment or access to it.

Opioids unavailable in the patient's pharmacy.

Unaffordable medication.

Flexibility is the key to managing cancer pain. As patients vary in diagnosis, stage of disease, responses to pain and interventions, and personal preferences, so must pain management. The recommended clinical approach outlined below emphasizes a focus on patient involvement.

1.

Ask about pain regularly. Assess pain and associated symptoms systematically using brief assessment tools. Assessment should include discussion about common symptoms experienced by cancer patients and how each symptom will be treated.[3,4] Asking a patient to identify his or her most troublesome symptom is also of clinical value because the most troublesome symptom is not always the most severe, as demonstrated in a survey of 146 patients in the palliative phase of treatment for lung, gastrointestinal, or breast cancer.[11]

2.

Believe patient and family reports of pain and what relieves the pain. (Caveats include patients with significant psychological/existential distress and patients with cognitive impairment.)[12,13]

3.

Choose pain-control options appropriate for the patient, family, and setting.

4.

Deliver interventions in a timely, logical, coordinated fashion.

5.

Empower patients and their families. Enable patients to control their course as much as possible.

Highlights of Patient Management

Effective pain management is best achieved by a team approach involving patients, their families, and health care providers. The clinician should:

Initiate prophylactic anticonstipation measures in all patients (except those with diarrhea) before or during opiate administration. (Refer to the Constipation section in the Side Effects of Opioids section of this summary for more information.)

Discuss pain and its management with patients and their families.

Encourage patients to be active participants in their care.

Reassure patients who are reluctant to report pain that there are many safe and effective ways to relieve pain.

Consider the cost of proposed drugs and technologies.

Share documented pain assessment and management with other clinicians treating the patient.

Know state/local regulations for controlled substances.

In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.

Current Clinical Trials

Check NCI's list of cancer clinical trials for U.S. supportive and palliative care trials about pain that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Pain Assessment

Failure to assess pain is a critical factor leading to undertreatment. Assessment involves both the clinician and the patient. Assessment should occur at the following times:

At each clinical encounter.

At regular intervals after initiation of treatment.

At each new report of pain.

At a suitable interval after pharmacologic or nonpharmacologic intervention (e.g., 15–30 minutes after parenteral drug therapy and 1 hour after oral administration).

Effective pain management requires close monitoring of patient response to initiation of treatment. In a review of 1,612 patients referred to an outpatient palliative care center where patients with advanced cancer were seen by both a palliative care nurse and a physician, more than half of patients with moderate to severe pain did not respond to an initial palliative care consultation, with response defined as a two-point or more reduction or a 30% or more reduction from baseline. Also, one-third of patients with mild pain actually progressed to moderate to severe pain by the time of their first follow-up visit. The authors concluded that more frequent follow-up visits, calls, and interdisciplinary clinics should be considered in an effort to optimize pain control. The study also identified baseline pain intensity, fatigue, and Edmonton Symptom Assessment System symptom burden as factors predicting response.[1][Level of evidence: III]

Identifying the etiology of pain is important to its management. Clinicians treating patients with cancer should recognize the common cancer pain syndromes (see lists below). Prompt diagnosis and treatment of these syndromes can reduce morbidity associated with unrelieved pain. Distinct cultural components may need to be incorporated into a multidimensional assessment of pain.[2,3,4,5] Reviews of cancer pain with a focus on neuropathic pain describes pathophysiologies as well as available and investigational pharmacotherapies.[6,7][Level of evidence: II]

Common Pain Syndromes: Pain Associated with Tumor

Bone lesions/metastases

Bone marrow expansion

Vertebral syndrome

Local infiltration

Base of skull involvement

Visceral

Hepatic capsule distension

Retroperitoneal syndrome

Intestinal obstruction

Ureteral obstruction

Neuropathies/plexopathies

Cranial neuropathies

Leptomeningeal disease

Base of skull metastases

Mononeuropathies

Polyneuropathies

Brachial, cervical, sacral

Cauda equina syndrome

Paraneoplastic syndrome

Osteoarthropathy

Gynecomastia

Sensorimotor neuropathy

Common Pain Syndromes: Pain Secondary to Treatment

Post–radiation therapy

Enteritis

Radiation fibrosis

Osteoradionecrosis

Myelopathy

Neuropathy/plexopathies

Brachial, sacral

Pain flare after radiopharmaceutical

Radiation-induced cystitis

Postchemotherapy

Arthralgia, myalgia

Aromatase inhibitors

Avascular necrosis

Chronic abdominal pain

Mucositis

Neuropathy

Platinum-based products: Cisplatin, carboplatin, oxaliplatin

Taxanes: Paclitaxel, docetaxel

Vinca alkaloids: Vincristine, vinblastine

Epothilones: Ixabepilone

Others: Bortezomib, lenalidomide, thalidomide

Post–hormonal therapy

Bone pain flare

Arthralgia, myalgia

Postsurgery

Acute postoperative or procedural pain

Phantom limb pain/postamputation pain

Postnephrectomy syndrome

Postmastectomy syndrome

Postthoracotomy syndrome

Post–radical neck dissection

Pelvic floor myalgia

Bisphosphonates

Bone pain, osteonecrosis

Initial Assessment

The goal of the initial assessment of pain is to characterize the pathophysiology of the pain and to determine the intensity of the pain and its impact on the patient's ability to function. For example, one study evaluated the association between psychological distress and pain in 120 patients with advanced cancer. Pain intensity and pain that interfered with walking ability, normal work, and relations with other people, as measured by the Brief Pain Inventory (Greek version), were found to be significant predictors of anxiety, as measured by the Hospital Anxiety and Depression Scale on multivariate analysis. Using the same tools, the authors also found pain that interfered with enjoyment of life was a predictor of depression.[8][Level of evidence: II] Factors that may influence analgesic response and result in persistent pain include changing nociception due to disease progression, intractable side effects, tolerance, neuropathic pain, and opioid metabolites.[9][Level of evidence: IV] The following are essential to the initial assessment:

The experience of cancer pain is complex and includes physical, psychosocial, and spiritual dimensions. There is no universally accepted pain classification measure that assists with predicting the complexity of pain management, particularly for cancer pain patients, who may be more difficult to treat. Clinicians and researchers lack a common language to discuss and compare outcomes of cancer pain assessment and management. Oncologists use the tumor, nodes, metastases (TNM) system as a universal language to describe a variety of cancers. The need for a similar classification system for cancer pain resulted in the development of the Edmonton Staging System.[11,12] This system has been further refined in two reports that have gathered construct validity evidence using an international panel of content experts [13] and a multicenter study to determine interrater reliability and predictive value.[14] The development of an internationally recognized classification system for cancer pain could play a significant role in improving the assessment of cancer pain, allow a more meaningful assessment of clinical prognosis and treatment, and better enable researchers to compare results with regard to cancer pain management.[15][Level of evidence: II]

Patient Self-report

The mainstay of pain assessment is the patient self-report; however, family caregivers are often used as proxies for patient reports, especially in situations in which communication barriers exist, such as cognitive impairment or language difficulties. Family members who act as proxies typically, as a group, report higher levels of pain than patient self-reports, but there is individual variation.[16,17][Level of evidence: II] Differences in clinician assessment of pain intensity are also significant. A retrospective review of 41 patient charts using pain ratings of palliative care consultants as the gold standard found high agreement with assessments performed by bedside nurses (registered nurses [RNs] and clinical nurse assistants [CNAs]) when pain was not present or was mild but poor agreement for moderate or severe pain (sensitivity: RNs, 45%; CNAs, 30%).[18][Level of evidence: III]

Pain assessment tools may be unidimensional or multidimensional. Multiple assessment tools exist. Among the more commonly used bedside tools are numeric rating scales, verbal rating scales, visual analog scales, and picture scales.[19,20][Level of evidence: IV] Pain intensity at initial assessment has been demonstrated to be a significant predictor of subsequent pain management complexity (i.e., the need for more pharmacological and multidimensional approaches) and length of time to achieve stable pain control.[21][Level of evidence: II] To enhance pain management across all settings, clinicians should teach families to use pain assessment tools in their homes. The clinician should help the patient to describe:

Pain

Listen to the patient's descriptive words about the quality of the pain; these provide valuable clues to its etiology. Elicit the temporal features including onset, duration, and diurnal variation. Ask about breakthrough pain (BP) or episodic pain (EP) (a transitory increase in pain that occurs in addition to persistent pain). Some patients may have EP without persistent pain.[22][Level of evidence: IV] The prevalence of BP-EP varies widely, depending on which definition is used and based on the clinical scenario and cultural setting. An appropriately designed, cross-sectional, multicenter study that evaluated BP-EP in patients with chronic cancer-related pain was completed.[23] The primary aim of the study was to assess the prevalence and characteristics of BP-EP on the basis of clinical assessment and through the use of a previously validated, culturally adapted tool, the Questionnaire for Intense Episodic Pain (QUDEI-Italian), which utilizes a patient interview technique. Physicians who participated in the study were trained to define and recognize BP-EP. Patient evaluation and use of the questionnaire were carried out by different sets of providers. There was an estimated prevalence of 73% when a BP-EP diagnosis was made by physicians and 66% when the QUDEI was applied. When patients with baseline pain levels of 6 or lower (based on a numerical rating scale from 0 to 10) were analyzed, the physician prevalence decreased to 67%, versus 60% with tool utilization. The authors concluded that because of the frequent occurrence of BP-EP, a more widely accepted general definition of this phenomenon and specific validated tools to assist in education and screening are needed.[23]

Location

Ask the patient to indicate the exact location of the pain on his or her body, or on a body diagram, and whether the pain radiates.

Changes in Pattern

Changes in pain pattern or the development of new pain should trigger diagnostic reevaluation and modification of the treatment plan. Persistent pain indicates the need to consider other etiologies (e.g., related to disease progression or treatment) and alternative (perhaps more invasive) treatments.

Intensity or Severity

Encourage the patient to keep a log of pain-intensity scores to report during follow-up visits or by telephone. Examples of simple self-report pain-intensity scales include the simple, descriptive, numeric, and visual analog scales.

Aggravating and Relieving Factors

Ask the patient to identify factors that cause the most pain and also what relieves the pain.

Cognitive Response to Pain

Cognitive appraisals of pain can be based on a range of psychological variables such as perceived control, meaning attributed to pain experience, fear of death, and hopelessness.[24] All these variables appear to contribute to the experience of cancer pain and suffering. A study of women with metastatic breast cancer found that although the site of metastasis did not predict the intensity of pain report, greater depression and the belief that pain represented the spread of disease significantly predicted the degree of pain experienced.[25] It was also reported that patients who thought that their pain represented disease progression reported more pain-related interference with function.[26][Level of evidence: II]

Cognitive Impairment

Note behavior that suggests pain in patients who are cognitively impaired or who have communication problems relating to education, language, ethnicity, or culture. Cognitive impairment itself and the degree of cognitive impairment may impact patient self-report of pain. Preliminary data suggest that mild degrees of cognitive impairment are associated with increased intensity of pain-report in older patients with cancer who are receiving hospice care.[16] In contrast, cognitively impaired nursing home residents are less likely to report pain. Use appropriate (e.g., simpler or translated) pain assessment tools.

Goals for Pain Control

Document the patient's preferred pain assessment tool and the goals for pain control (such as scores on a pain scale).

Encourage use of the pain diary: The daily pain diary is a well-established tool in symptom management research and in clinical practice. Benefits of using a pain diary include heightened awareness of pain, guidance for pain management behaviors, enhanced sense of control, and a tool for communication.[27] It is difficult to get good pain-diary compliance with adolescents who are experiencing intense chronic pain.

Physical Examination

A thorough physical examination is required to determine the pathophysiology of pain. Specific features of the neurologic examination such as altered sensation (hypoesthesia, hyperesthesia, hyperpathia, allodynia) in a painful area are suggestive of neuropathic pain. Physical findings of tumor growth and metastasis are also important to identify.

Information obtained from the synthesis of history, physical examination, and diagnostic evaluations is used to generate a pain diagnosis with respect to etiology (cancer, its treatment, or other) and pathophysiology (somatic, visceral, and/or neuropathic). This diagnosis, in conjunction with contributing psychosocial and spiritual factors, is used to generate a comprehensive pain treatment plan.

Assessment of the Outcomes of Pain Management

Pain-related outcomes: Clinicians should document and be aware of outcomes of pain therapy. It is helpful to think of pain-related outcomes as primarily measured in two ways: decreased pain intensity and improvement in psychosocial functioning. Using rating scales of pain intensity at its worst and on average and using pain interference scales can help clinicians monitor outcomes. Measurement of the percentage of pain relief is also useful, though measuring patient satisfaction is less useful because of the low expectations patients sometimes hold for pain control.[28,29]

Drug-taking outcomes: Clinicians prescribing chronic opioids should also monitor and document patients' drug-taking behaviors. Outcomes related to addiction in cancer patients are rare but nonetheless should be periodically assessed; these assessments can be reassuring to patients. Tolerance and dependence are not addiction related. Documentation of patients' compliance with regard to changes in dosing and duration of prescriptions is essential in all pain practice.

The clinical assessment of drug-taking behaviors in medically ill patients with pain is complex. Aberrant drug-taking behavior from cancer pain management is related to premorbid history of drug addiction and the likelihood of other pain treatment. A pilot questionnaire was used to characterize drug-related behaviors and attitudes in cancer and AIDS patients. Despite limitations, this study highlights wide potential variation among different palliative care populations in patterns of past and present aberrant drug-taking behaviors and the need for a clinically useful screening approach. The implications for psychosocial and pharmacological management of symptoms such as pain, as well as any aberrant behavior, remain unclear.[30,31,32]

Previous drug abuse is likely to lead to specific needs for appropriate dosing during cancer pain therapy. A prospective open-label study compared morphine dosage and effectiveness in AIDS patients with and without previous substance abuse. Results demonstrated that both groups benefited, but patients with a history of drug use required and tolerated substantially higher morphine doses to achieve stable pain control.[33][Level of evidence: II] This study should increase confidence in providing appropriate pain management to patients who have a history of drug use.[34][Level of evidence: IV]

Pharmacologic Management

Basic Principles of Cancer Pain Management

The World Health Organization (WHO) has described a three-step analgesic ladder as a framework for pain management.[1] It involves a stepped approach based on the severity of the pain. If the pain is mild, one may begin by prescribing a Step 1 analgesic such as acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). Potential adverse effects should be noted, particularly the renal and gastrointestinal adverse effects of the NSAIDs. If pain persists or worsens despite appropriate dose increases, a change to a Step 2 or Step 3 analgesic is indicated. Most patients with cancer pain will require a Step 2 or Step 3 analgesic. Step 1 can be skipped in favor of Step 2 or Step 3 in patients presenting at the onset with moderate-to-severe pain. At each step, an adjuvant drug or modality such as radiation therapy may be considered in selected patients. WHO recommendations are based on worldwide availability of drugs and not strictly on pharmacology.

Analgesics should be given "by mouth, by the clock, by the ladder, and for the individual."[1] This requires regular scheduling of the analgesic, not just as needed. In addition, rescue-doses for breakthrough pain need to be added. The oral route is preferred as long as a patient is able to swallow. Each analgesic regimen should be adjusted for the patient's individual circumstances and physical condition.

Acetaminophen and Nonsteroidal Anti-inflammatory Drugs

NSAIDs are effective for relief of mild pain and may have an opioid dose–sparing effect that helps reduce side effects when given with opioids for moderate-to-severe pain. Acetaminophen is included with aspirin and other NSAIDs because it has similar analgesic potency, though it lacks peripheral anti-inflammatory activity.[2][Level of evidence: I] Side effects can occur at any time, and patients who take acetaminophen or NSAIDs, especially elderly patients, should be followed up carefully.[3,4,5] There is growing debate about whether NSAIDs are useful and have significant opioid-sparing effects. One meta-analysis [6] suggests that the usefulness of NSAIDs is limited and that they do not significantly spare opioid doses. Another study suggests that NSAIDs are useful and reduce the need for opioid dose increases; however, only patients with pain progression after 1 week of opioid stabilization were selected for the study.[7][Level of evidence: I] Patients taking NSAIDs are at risk for platelet dysfunction that may impair blood clotting. Table 1 lists NSAIDs with minimal antiplatelet activity.

The coxibs are a subclass of NSAIDs designed to selectively inhibit cyclooxygenase-2 (COX-2).[8] Development of these drugs was based on the hypothesis that COX-2 was the source of prostaglandins E2 and I2, which mediate inflammation, and that COX-1 was the source of the same prostaglandins in gastric epithelium, with the potential advantage of less gastrointestinal ulceration and bleeding and the absence of platelet inhibition over traditional NSAIDs. Direct comparisons between COX-2 inhibitors are few. A systematic meta-analysis of COX-2 inhibitors compared with traditional NSAIDs or different COX-2 inhibitors for postoperative pain suggests that rofecoxib, 50 mg, and parecoxib, 40 mg, are equipotent to traditional NSAIDs for postoperative pain after minor and major surgical procedures and have a longer duration of action after dental surgery. Rofecoxib was found to provide superior analgesic effect compared with celecoxib, 200 mg. There were insufficient data to comment on toxicity.[9][Level of evidence: I]

There are three coxibs that were approved by the U.S. Food and Drug Administration (FDA): celecoxib, rofecoxib, and valdecoxib. On September 30, 2004, rofecoxib was withdrawn from the market after a study demonstrated that subjects in a colon cancer prevention trial who took the drug at higher-than-typical doses on a long-term basis had a significant increase in the incidence of serious thromboembolic complications. The question that remains unanswered is whether the increased risk applies to all COX-2 inhibitors, with the caution that the burden of proof rests with those who might claim that this is a problem for rofecoxib alone and does not extend to other coxibs.[8,10] On April 7, 2005, valdecoxib was withdrawn from the market. FDA is also asking manufacturers of all marketed prescription NSAIDs, including celecoxib (Celebrex), to revise the labeling (package insert) for their products to include a boxed warning, highlighting the potential for increased risk of cardiovascular events and/or the serious, potentially life-threatening gastrointestinal bleeding associated with use of these drugs.

Dosage

Use patient response to determine the effective dosing interval for aspirin, acetaminophen, and other NSAIDs listed in Table 1. When pain relief is not attained with the maximum dosage of one NSAID, try other drugs within this category before abandoning NSAID therapy.

Route of administration

Use readily available oral tablets, capsules, or liquid. During intervals of nausea and vomiting, use suppositories, unless the nausea is NSAID related. Ketorolac tromethamine is the only NSAID available for parenteral use.

Observe patients carefully for adverse effects, which range from mild gastrointestinal discomfort to more serious problems, including the following:

Gastric ulceration.

Hepatic dysfunction.

Myocardial infarction.

Renal failure.

Because both NSAIDs and other drugs (e.g., warfarin, methotrexate, digoxin, cyclosporine, oral antidiabetic agents, and sulfonamide-containing drugs) are highly protein-bound, there is potential for altered efficacy or toxicity when they are given simultaneously.

Opioids, the major class of analgesics used in management of moderate-to-severe pain, are effective, are easily titrated, and have a favorable benefit-to-risk ratio.

The predictable consequences of long-term opioid administration—tolerance and physical dependence—are often confused with psychological dependence (addiction) that manifests as drug abuse. This misunderstanding can lead to ineffective prescribing, administering, or dispensing of opioids for cancer pain. The result is undertreatment of pain.[11]

Clinicians may be reluctant to give high doses of opioids to patients with advanced disease because of a fear of respiratory depression. Many patients with cancer pain become opioid tolerant during long-term opioid therapy. Therefore, the clinician's fear of shortening life by increasing opioid doses is usually unfounded.

Opioid types

Opioids are classified as full morphine-like agonists, partial agonists, or mixed agonist-antagonists, depending on the specific receptors to which they bind and their activity at these receptors. The benefits of using opioids and the risks associated with their use vary among individuals.

Morphine is the most commonly used opioid in cancer pain management, largely for reasons of availability and familiarity;[12] however, it is useful to be familiar with more than one type of opioid. Wide interindividual variability in response to both the analgesic and adverse effects of opioids is recognized.[13] Some patients may not experience adequate pain control despite appropriate dose adjustments, while others may develop intolerable adverse effects to one particular opioid (see below). Alternative opioids include hydromorphone, oxycodone, oxymorphone, methadone, and fentanyl. Knowledge of several medications and formulations gives the caregiver much more flexibility in tailoring a regime to a particular patient's needs.

Short-acting opioids are generally recommended when opioid therapy is being initiated for the first time or when patients are medically unstable or the pain intensity is highly variable. Once stable, patients can be switched to a controlled-release or slow-release formulation. This is more convenient and promotes compliance. (Refer to Table 3 in the Principles of Opioid Administration section of this summary for more information.)

Full agonists

Morphine, hydromorphone, codeine, oxycodone, oxymorphone, hydrocodone, methadone, levorphanol, and fentanyl are classified as full agonists because their effectiveness with increasing doses is not limited by a ceiling. Full agonists will not reverse or antagonize the effects of other full agonists given simultaneously.

Morphine

The most commonly used opioid, morphine, is readily available in several forms, including sustained-release (8–24 hours duration of effectiveness) formulations for oral administration.

Other agonists

For the patient who experiences dose-limiting side effects with one oral opioid (e.g., hallucinations, nightmares, dysphoria, nausea, or mental clouding), other oral opioids should be tried before abandoning one route in favor of another.

Methadone

Methadone has had a revival in interest for the management of cancer pain. Published reports have been in the form of case reports,[14,15,16,17,18,19,20][Level of evidence: III] outcome surveys,[21,22,23,24,25][Level of evidence: II][Level of evidence: III] and reviews.[26,27,28][Level of evidence: IV] Success has been reported with oral, intravenous (IV), and suppository methadone use. Subcutaneous methadone has been reported to cause tissue irritation at the injection site but has been used effectively in some patients without clinically significant local toxicity.[29][Level of evidence: II]

Methadone is a synthetic opioid agonist that has been reported to have a number of unique characteristics. These include excellent oral and rectal absorption, no known active metabolites, prolonged duration of action resulting in longer administration intervals, and lower cost than other opioids. Methadone is available as a pill, an elixir, and for parenteral use. Methadone has an average oral bioavailability of approximately 80% (range, 41%–99%).[30]

Morphine is the international gold standard for first-line treatment of cancer pain. Methadone, however, can be considerably less expensive than existing rapid-release or sustained-release morphine or other opioid options. A randomized trial of 103 patients compared the effectiveness and side effects of morphine and methadone as first-line treatments for cancer pain. The outcome of successful pain management was similar for both groups; however, there were significantly more opioid-related dropouts in the methadone group. This study did not demonstrate superior analgesic effectiveness or overall tolerability of methadone over morphine as a first-line treatment for cancer pain. Despite this finding, the authors of this report suggested that study limitations did not allow definitive conclusions that methadone could not be a useful first-line opioid. Further research exploring other doses and schedules of methadone should still be explored.[31][Level of evidence: I]

Because of its long and unpredictable half-life and relatively unknown equianalgesic dose as compared with other opioids, methadone has been generally used by pain specialists with experience in its use. The utility of methadone in cancer pain and difficult cancer pain syndromes such as neuropathic pain has become more widely appreciated and has gained increasing acceptance for use in hospital and hospice settings and by clinicians who are not pain specialists.[32][Level of evidence: II] The methadone preparation widely used in the United States is a racemic mix of the d-isomer and l-isomer of methadone. The d-isomer has antagonist activity at the N-methyl-D-aspartate (NMDA) receptor and may be beneficial in controlling neuropathic pain.

Another controversy related to methadone is the concern that this drug may be associated with a prolonged QTc interval and may lead to torsades de pointes and ventricular arrhythmia. A number of studies have raised this concern. A series of 132 patients taking methadone revealed statistically significant mean increases in QTc of 10.2 to 13.2 milliseconds, yet no episodes of torsades de pointes were reported.[33][Level of evidence: III] This result raises the issue of the clinical significance of this effect. In another retrospective review of 520 patients treated with methadone for cancer pain, no change in QTc was seen in the 56 patients who had electrocardiograms 3 months before and after starting methadone.[34,35] Another study of 100 cancer patients revealed a baseline electrocardiogram in 28%, with only one demonstrating a clinically significant increase in QTc at week 2.[36] Avoidance of concomitant medications that prolong QTc interval [37] or that share common metabolism pathways with methadone [34] is recommended. In high-risk situations, clinicians could consider electrocardiogram monitoring and other clinical precautions such as correcting electrolyte abnormalities.

When converting from another opioid to methadone, the calculated equianalgesic dose ratio of methadone varies depending on the oral morphine-equivalent daily dose (MEDD) of the previous opioid.[38][Level of evidence: II];[22][Level of evidence: III] One guideline for choosing an appropriate initial dose of methadone based on the oral MEDD of the previous opioid is shown in Table 2. For example, a patient who has been using sustained-release morphine at 80 mg every 8 hours (240 mg/d) would be appropriately switched to methadone at a dose of 10 mg every 8 hours (30 mg/d, an 8:1 conversion ratio). In contrast, a patient who is taking sustained-release morphine at a total daily dose of 60 mg/d might be switched to an oral methadone dose of 5 mg every 8 hours (15 mg/d, a 4:1 conversion ratio).

Table 2. Method 1: Initial Methadone Dose Based on Oral MEDDa

b Great caution must be used when converting to methadone when very high opioid doses have been used. Often, only a portion of the total opioid dose is converted initially, with further conversions taking place over several days to weeks.

<30

2:1

30–99

4:1

100–299

8:1

300–499

12:1

500–999

15:1

>1,000

20:1 or greaterb

To be conservative, one might estimate that methadone is roughly twice as potent when administered via IV versus oral administration. Thus, a patient with well-controlled pain on a stable oral methadone dose of 10 mg every 8 hours might be given IV methadone at an initial dose of 5 mg every 8 hours if IV use is necessary. Subcutaneous use of methadone may cause skin irritation in some patients but has been used successfully.

In addition to the method described in Table 2, several methods of switching to methadone have been proposed.[22,40,41][Level of evidence: III];[42,43][Level of evidence: II];[44] Some rely on patient-controlled analgesia with fixed doses and flexible intervals, some require fixed intervals and fixed doses, while others stagger the conversion over a few days. Whatever method is chosen, this kind of switch can be safe and effective as long as regular assessments are provided over time, and there is an appreciation of the equianalgesic dose ratio of methadone to morphine in opioid-tolerant patients.

One approach calls for a gradual switch over 3 to 5 days to decrease the risk of relative overdosing. An equianalgesic dose of methadone is first calculated, using an equianalgesic dose ratio of morphine to methadone of 10:1 (i.e., methadone is approximately ten times more potent than morphine). The caveat in using a ratio of 10:1 is that variations in ratios have been noted, depending on the dose of the previous opioid. The ratio may be much higher (12:1 or even higher) in patients being switched from high doses of morphine to methadone. The following example is given to illustrate this method:

A patient who is on the equivalent of 450 mg/d of oral morphine (quick-release morphine 75 mg orally every 4 hours) needs to be switched to methadone. Using a ratio of 10:1, the predicted equivalent daily oral dose of methadone, once the switch is completed, will be 45 mg.

On day 1 of the switch, the daily morphine dose is reduced by one-third to approximately 300 mg (morphine 50 mg orally every 4 hours), and one-third of the predicted daily methadone dose is added, divided into three doses per 24 hours (i.e., methadone 5 mg orally every 8 hours). Morphine continues to be given for rescue doses.

On day 2 of the switch, the patient is reassessed. If no problems have developed, the morphine dose is reduced by another third (i.e., morphine 25 mg orally every 4 hours), and the methadone dose is increased by another third (i.e., methadone 10 mg orally every 8 hours).

On day 3 of the switch, the patient is reassessed.

If there are complications such as significant somnolence, but the pain is still not under good control, the methadone dose is increased to 15 mg every 8 hours, and the morphine is discontinued.

A rescue dose of methadone or a short half-life opioid is added, as needed. The rescue dose is calculated at 5% to 15% of the total daily dose.

If the patient has good pain control but shows signs of relative overdosing (e.g., significant somnolence), the methadone dose is not increased (i.e., it remains at the day 2 level or may even be decreased, if needed), and the morphine is discontinued.

This approach calls for the previous dose to be discontinued and a single fixed-dose of methadone to be given at the start, calculated using an equianalgesic dose ratio of morphine to methadone of 10:1 (i.e., morphine 10 mg being roughly equivalent to 1 mg of methadone), but to a maximum of 50 mg of methadone per dose. After the initial single priming dose, the same dose is administered every 3 hours as needed. When the clinician observes the patient's demand for rescue doses reduces or stabilizes (indicating steady-state being reached), which is usually on day 4 to 7, the daily requirement is recalculated and the dose is given every 8 to 12 hours.

In this method, an opioid-naïve patient is started on 3 to 5 mg of methadone every 8 hours, and a nonnaïve patient is started on a dose of methadone that is equivalent to 50% of the estimated daily morphine dose. These doses are initially given for 3 days. Once the patient has acceptable pain relief for 6 to 8 hours, the dose is changed to a single fixed dose once a day and rescue doses are given as needed. This method is probably best suited for opioid-naïve patients (in relatively unlikely situations where more frequently used opioids such as morphine are not available) or patients who are, for one reason or another, being switched from relatively low doses of morphine or other opioids.

This method is suggested when patients are being switched from high equivalent daily doses of morphine (>600 mg/d orally). The morphine or other opioid the patient is receiving is stopped. Methadone at a dose of 5 to 10 mg orally is started every 4 hours and rescue doses of 5 to 10 mg every hour are allowed as needed. On the second to third days of the switch, the methadone dose is increased by up to 30% every 4 hours until sufficient pain relief is achieved and no significant adverse effects are noted. After exactly 72 hours following the switch to methadone, the dose is changed from every 4 hours to every 8 hours, and the interval of rescue doses is increased to every 3 hours as needed at the same single dose as established on days 2 to 3. The dose can then be increased by up to 30% if further upward titration is required.

In some countries, there are restrictions on the ability of physicians to prescribe methadone that do not apply to other opioids. In the United States, this pertains to methadone for maintenance of addiction. Methadone is not restricted when used for pain management; however, physicians should carefully document the use of methadone.[45] It should be noted that ratios are different for switching from methadone to a morphine-like opioid.[22]

Meperidine (Demerol)

Useful for brief courses (a few days) to treat acute pain, meperidine is not recommended in treating persistent cancer pain because of its short duration of action (2.5–3.5 hours) and its neurotoxic metabolite, normeperidine. Accumulation of this metabolite, particularly when renal function is impaired, causes central nervous system (CNS) stimulation that may lead to delirium or seizures. Seizures are typically preceded by development of multifocal myoclonus, which can serve as a warning sign.

Tapentadol

Tapentadol is a centrally acting analgesic with a dual mode of action, as a mu-opioid receptor agonist and norepinephrine reuptake inhibitor.[46,47] In 2009, the FDA approved immediate-release tapentadol for the management of moderate to severe pain. In August 2011, the FDA also approved the extended-release formulation of tapentadol for the management of moderate to severe chronic pain. As with other mu-opioid receptor agonists, use of tapentadol may be associated with respiratory depression, sedation, nausea, and constipation. No studies have been published in cancer pain. In the noncancer setting, there appear to be fewer gastrointestinal adverse effects with tapentadol than with oxycodone.[46,47] Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs (this includes serotonin reuptake inhibitors; serotonin and norepinephrine reuptake inhibitors; tricyclic antidepressants; triptans; drugs that affect the serotonergic neurotransmitter system, such as mirtazapine, trazodone, and tramadol; and drugs that impair metabolism of serotonin). Extended-release tapentadol has not been evaluated in patients with a predisposition to seizure disorder.

Tramadol

Tramadol can be considered an atypical opioid analgesic that has a dual action. It is a weak mu-opioid agonist that also inhibits the reuptake of norepinephrine and serotonin.[48][Level of evidence: IV];[49][Level of evidence: I] It is believed that both mechanisms work synergistically to provide analgesic benefit with a potency that is approximately one-tenth that of morphine [50][Level of evidence: II] and approximately equivalent to codeine. The most common side effects reported with tramadol are drowsiness, constipation, dizziness, nausea, and orthostatic hypotension.[48] There is also a risk of precipitating seizures in patients with a previous history or in patients who are receiving medications that could reduce the seizure threshold. The use of other serotonergic medications (e.g., selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]) together with tramadol has the potential to increase the risk of the serotonin syndrome. Tramadol is available in short- and long-acting formulations and in fixed combination with acetaminophen. The recommended starting dose of oral tramadol is 50 mg 1 or 2 times a day, with gradual titration up to a maximum of 400 mg/d.[48] There is also the option of using tramadol via the rectal or subcutaneous route in patients who are unable to tolerate oral medication.[51][Level of evidence: I];[52]

Partial agonists

Partial agonists such as buprenorphine are subject to a ceiling effect and are less effective analgesics than full agonists at opioid receptors. A 7-day buprenorphine patch is available; the maximum dose is 20 μg per hour because of the potential for prolonged QTc wave interval.[53]

Mixed agonist-antagonists

Mixed agonist-antagonists block or are neutral at one type of opioid receptor while activating a different opioid receptor. Mixed agonist-antagonists are contraindicated for use in the patient receiving an opioid agonist because they may precipitate a withdrawal syndrome and increase pain. Mixed agonist-antagonists include pentazocine (Talwin), butorphanol tartrate (Stadol), dezocine (Dalgan), and nalbuphine hydrochloride (Nubain). Their analgesic effectiveness is limited by a dose-related ceiling effect.

Principles of opioid administration

Most patients with cancer pain require fixed-schedule dosing to manage the constant pain and prevent the pain from worsening.[54][Level of evidence: II] An Italian study of patients whose baseline pain was well controlled on morphine when admitted to a palliative care unit found that most episodes of breakthrough pain were rapidly controlled with IV morphine equivalent to 20% of the calculated equianalgesic total daily dose. Adverse effects were uncommon.[55][Level of evidence: II] An as-needed rescue dose (breakthrough dose) should be combined with the regular fixed-schedule opioid to control the episodic exacerbation of pain, often referred to as breakthrough pain. When this pain is elicited by an action such as weight-bearing, breathing, or defecation, it is termed incident pain. Rescue or breakthrough doses can be given hourly or more frequently as needed, depending on route of administration, pharmacokinetic properties of the drug, and presence or absence of side effects. The breakthrough dose is generally calculated to be 10% to 20% of the total dose of the fixed schedule.[56][Level of evidence: III] Adherence rates are improved when patients are prescribed around-the-clock opioids compared with as-needed prescribing.[57][Level of evidence: I] Preliminary data suggest that the intensity of incident pain related to bone metastases may be diminished by increasing the dose of the scheduled opioid above that needed for control of baseline pain, while maintaining it below that associated with the development of limiting side effects.[58][Level of evidence: II]

Dosage

The appropriate dosing interval is determined by the opioid and formulation used. The analgesic effects of short-acting oral opioids such as morphine, hydromorphone, codeine, and oxycodone begin within a half hour after administration and last for approximately 4 hours. The dosing interval of these drugs is usually 4 hours. In patients given controlled-release formulations of morphine, hydromorphone, codeine, or oxycodone, relief should begin in 1 hour, peak in 2 to 3 hours, and last for 12 hours (controlled-release codeine is not available in the United States); these formulations are usually prescribed in 12-hour intervals. The analgesic effect of transdermal fentanyl begins approximately 12 hours after the application of the patch, peaks in 24 to 48 hours, and lasts for approximately 72 hours. Patches are therefore changed every 72 hours. In a select group of patients who consistently experience end-of-dose failure despite increases in the patch doses, the dosing interval can be increased to every 48 hours (<10% of patients on fentanyl patches). Transdermal fentanyl is not recommended for control of acute pain or poorly controlled pain because there is a delayed onset of action until reaching steady-state either with new use or with a change in the dose. Patients receiving transdermal fentanyl may be switched to a continuous IV or subcutaneous infusion of fentanyl using a conversion ratio of 1:1 to facilitate more rapid titration.[59][Level of evidence: III]

Dose titration

To date, dose titration is largely patient-driven, as determined by the balance of analgesia with side effects.[60][Level of evidence: II] For example, while morphine dose correlates with peak-and-trough plasma concentrations of a parent drug and its metabolites morphine-3-glucuronide and morphine-6-glucuronide, studies are conflicting with regard to the association between plasma levels of morphine and its metabolites versus analgesia as measured by pain scores.[61][Level of evidence: II] The strong opioid agonists have no maximum dose or ceiling dose. The appropriate dose is the amount of opioid that controls pain with the fewest side effects. Dose titration should continue until good pain relief is achieved or intolerable side effects develop that cannot otherwise be controlled. The goal is to achieve a favorable balance between analgesia and side effects through gradual adjustment of the dose. If analgesic tolerance appears to be occurring, the dose can be increased or consideration given to switching the opioid, especially if higher doses are required.

The severity of the pain and the opioid formulation chosen determine the rate of titration. The dose of immediate-release formulations can be increased on a daily basis if necessary until pain relief is adequate. Among patients receiving relatively low doses of opioids, those with uncontrolled moderate-intensity pain require daily increases of between 25% and 50% to their previous dose, while patients with severe uncontrolled pain may require a higher increase. At higher opioid doses, increases of 20% to 30% would be more prudent. Rapid dose escalation requires close monitoring for both efficacy and side effects. Preliminary data suggest that titration with sustained-release daily morphine is equivalent to titration with immediate-release morphine administered every 4 hours by an expert group of clinicians, but standard practice is to use a short-acting opioid for initial titration.[62][Level of evidence: I]

Occasionally, doses may need to be reduced or, rarely, stopped. This may occur when patients become pain free as a result of cancer treatment, including treatments such as nerve blocks and radiation therapy. Another time to consider reducing the dose is when a patient experiences significant opioid-related sedation that is accompanied by good pain control or when there is metabolite retention in the context of developing and/or worsening renal failure. In situations where interventions achieve complete pain relief, rapid opioid tapering rather than abrupt discontinuation is recommended to avoid opioid withdrawal symptoms.

Different types of opioids

The debate regarding whether any individual opioid causes fewer side effects or is more effective is characterized by much speculation but little clinical evidence. These inconclusive findings have prompted expert working groups of the European Association of Palliative Care to recommend that there is currently little evidence of the clinical superiority of one opioid over another regarding the side-effect profile and/or analgesia.[12,13] Even constipation and other side effects may be positively affected by a switch. Compared with morphine, fentanyl may cause less constipation.[63][Level of evidence: II];[64][Level of evidence: I] Studies suggesting that oxycodone and hydromorphone may cause less nausea and hallucinations than morphine [65] are juxtaposed with other studies that found no significant differences between them.[66,67,68][Level of evidence: I] One study found that transdermal fentanyl was better tolerated than sustained-release oral morphine and equally effective.[69][Level of evidence: I]

Health professionals should check current recommendations for opioid use in older people, children, people who are cognitively impaired, and known or suspected drug abusers.

Opioid switching (Opioid rotation)

A series of case reports have demonstrated the clinical problem of inadequate pain control with escalating opioid doses in the presence of dose-limiting toxic effects, including hallucinations, confusion, hyperalgesia, myoclonus, sedation, and nausea.[17,23,70,71,72][Level of evidence: III] It was suggested that these problems could be managed by switching to an alternative opioid, with the result being improved pain management and decreased toxic effects. The improvement with opioid switching, although predominantly demonstrated initially with morphine, has also been reported with other opioids.[73,74,75][Level of evidence: III];[76][Level of evidence: II] A retrospective review over a 1-year period in a pediatric oncology center supports efficacy of this technique in children, with resolution of adverse opioid effects, largely pruritus, achieved in 90% of patients, while maintaining pain control.[77][Level of evidence: III]

Guidelines for switching from one opioid to another

Guidelines for opioid switching are intended to reduce the risk of relative overdosing or underdosing as one opioid is replaced by another. These guidelines require a working knowledge of an equianalgesic-dose table.[13,78][Level of evidence: IV] The equianalgesic-dose table provides only a broad guide for dose selection when switching from one opioid to another. Wide ranges in interindividual responses to the various opioids have been noted.[78][Level of evidence: IV] Therefore, because of incomplete cross-tolerance in most cases, the calculated dose-equivalent of a new drug must be reduced by 25% to 50% to ensure safety. These figures are based on clinical experience rather than empiric data. The selection of an alternative opioid is largely empirical. There is little clinical evidence to indicate that one opioid has therapeutic superiority over another opioid. A patient, for example, who requires a switch from morphine to another opioid can be switched to hydromorphone, oxycodone, fentanyl, or methadone.[79][Level of evidence: III];[80,81][Level of evidence: II] In one prospective study of 186 cancer patients being treated with morphine, 25% did not respond and required switching to another opioid (oxycodone). The primary reasons for switching included pain, confusion, drowsiness, nightmares, and nausea. Of the 47 patients who required switching to an alternative opioid, 37 (79%) obtained good relief. This result provides beginning evidence for the prevalence of the need to switch, as well as determining the success rate once switching occurs.[82][Level of evidence: II] Patients should be followed closely after a switch and should be reassessed, and the new opioid dose should be adjusted according to the intensity of pain and lack or presence of adverse effects.

Note: The values that appear in Table 3 are NOT recommended starting doses. Opioid doses are highly variable and should be based on the individual's previous responses and overall condition. Important cautions are contained in the footnotes.

Table 3. Approximate Dose Equivalents for Opioid Analgesicsa

Drug

Oral Dose (mg)

Parenteral Doseb

IV = intravenous; NA = not available.

a Published tables vary in the suggested doses that are equianalgesic to morphine. Many of these doses are based on clinical consensus rather than well-controlled trials. Clinical response is the criterion that must be applied for each patient; titration to clinical response is necessary. Because there is not complete cross-tolerance among these drugs, it is usually necessary to use a lower-than-equianalgesic dose when changing drugs and re-titrate according to response.

b Parenteral dosing includes IV and subcutaneous administration. Onset and duration may vary slightly between these routes; however, doses remain approximately equal. The intramuscular route is not recommended because of variability in uptake of the drug and painful injection.

c Caution: For morphine, hydromorphone, and oxymorphone, rectal administration is an alternate route for patients unable to take oral medications. Equianalgesic doses may differ from oral to parenteral doses because of pharmacokinetic differences. Note: A short-acting opioid should normally be used for initial therapy of moderate-to-severe pain.

d Caution: Doses of aspirin and acetaminophen in combination opioid/NSAID preparations must be adjusted to the patient's body weight.

e Transdermal fentanyl is an alternative. Transdermal fentanyl dosage is not calculated as equianalgesic to a single morphine dosage but is calculated based on a 24-hour opioid dose. See package insert for dosing calculations. Transdermal fentanyl should not be used in opioid-naïve patients.

f Transmucosal and buccal fentanyl are also available and indicated for breakthrough pain, although they are not bioequivalent. Titration of either should be conducted gradually; neither should be used in opioid-naïve patients.

g Caution: Methadone is much more potent than indicated in older published literature. On average, it is ten times more potent than morphine. However, its potency relative to morphine is not linear. When morphine at lower doses (e.g., 30–60 mg/d orally) is switched to methadone, the potency may be 3 to 5 times; when switched from high doses (e.g., >300 mg/d orally), the potency may be 12 times or even higher.

h Caution: The oral to IV dose ratio of methadone is not well established. The IV route is very seldom used, except in cancer centers with pain service familiar with parenteral methadone. Intravenous use of methadone in combination with chlorobutanol is associated with QTc wave prolongation.[37][Level of evidence: III] Subcutaneous administration may cause irritation.

It has been suggested that a less complicated approach than opioid switching would be reassessment of the clinical situation and use of adjuvant analgesics, decreasing the opioid dose if possible, use of medical management for opioid-related side effects, and correction of any contributing metabolic abnormalities.[83,84] Nevertheless, there does appear to be an emerging consensus that opioid switching does have a useful role when pain control remains inadequate with escalating opioid doses and opioid use results in unacceptable opioid-related side effects.[83,84,85][Level of evidence: IV]

Morphine, as the strong opioid of choice for the management of cancer pain, was used increasingly during the 1970s and 1980s.[86][Level of evidence: IV] Associated with this increasing experience was the clinical observation of the risk of accumulation of morphine metabolites, particularly in the presence of renal impairment. Morphine-6-glucuronide, an analgesic metabolite, was recognized as having a useful role in enhancing analgesia. A number of reports, however, have described seizures, cognitive impairment, nausea, and problems of myoclonus that were associated with accumulation of morphine-6-glucuronide.[86,87,88][Level of evidence: IV];[89,90,91][Level of evidence: II];[92,93][Level of evidence: III]

The potential role of morphine metabolites, in particular the ratio of 3-glucuronide to 6-glucuronide in the development of opioid-related toxicity, has been reported. The literature on this issue has been somewhat controversial. There is no disagreement that morphine metabolites increase in the presence of deteriorating renal function; however, there has been conflicting evidence regarding the role and ratios of the metabolites in patients exhibiting both a poor response to increasing morphine doses and associated toxicity.[94,95,96,97,98]

Switching from one opioid to another requires familiarity with a range of opioids and the use of opioid dose-conversion tables.[13,78] When using these ratios, it must be understood that the guidelines should be reviewed and the patients should be monitored more closely during the switching phase. One review has highlighted some important issues related to these tables.[78] Wide ranges in ratios are noted. In the case of methadone, it is much more potent than previously thought (on average ten times more potent), and its equianalgesic dose-ratio compared to other opioids changes according to the dose of the previous opioid; the higher the dose, the higher the ratio. (Note that potency does not denote more effectiveness but denotes the equivalent dose required to obtain the same effect.)

Route of administration

Oral administration is preferred in patients with intact gastrointestinal tracts because it is convenient and usually inexpensive. When patients cannot take oral medications, other less invasive routes (e.g., rectal or transdermal) should be offered. Parenteral methods should be used only when simpler, less demanding, and less costly methods are inappropriate, ineffective, or unacceptable to the patient. In general, assessing the patient's response to several different oral opioids is advisable before abandoning the oral route in favor of anesthetic, neurosurgical, or other invasive approaches.

Rectal

Use this safe, inexpensive, effective route for delivery of opioids as well as nonopioids when patients have nausea or vomiting. Rectal administration is inappropriate for the patient who has diarrhea, anal/rectal lesions, mucositis, thrombocytopenia, or neutropenia. The use of suppositories is not always culturally acceptable and may not be practical for patients who are obese, have fractures, are physically unable to place the suppository in the rectum, or prefer other routes. When changing from the oral to the rectal route, begin with the same dosage as had been given orally, then titrate as needed.

Transdermal

Fentanyl patches are formulated to provide analgesia lasting up to 72 hours. This preparation is not suitable for rapid dose titration and should be used for relatively stable analgesic requirements when rapid increases or decreases in dosage are not likely to be needed.[99][Level of evidence: I];[100] In the chronic setting, considerable inter- and intraindividual variability may exist in the rate of absorption of fentanyl from transdermal patches in patients receiving a stable dose of transdermal fentanyl.[101,102][Level of evidence: II] Based on a case series, it has been proposed that conversion from transdermal to IV fentanyl using a 1:1 conversion ratio can be safe and effective during acute exacerbations of cancer pain.[59][Level of evidence: III] Although other opioids such as morphine are sometimes compounded into gel form for transdermal application, bioavailability studies demonstrate plasma levels of drug below the level of detection. This practice should not be supported.[103][Level of evidence: I]

Transdermal buprenorphine has been used with success for the treatment of cancer-related pain in Europe, although studies in the United States are not yet published.[104][Level of evidence: I]

Transmucosal/Buccal (fentanyl)

Oral transmucosal fentanyl citrate is used for the relief of breakthrough pain. The lipid solubility of fentanyl allows rapid onset of pain relief. In open-label studies, 72% to 92% of patients found a dose that provided relief from breakthrough pain. Side effects in these studies were consistent with other opioid therapies, including sedation, constipation, stomatitis, and nausea.[105,106][Level of evidence: II] There is growing interest in the use of rapidly acting, highly lipophilic opioids such as fentanyl for the management of difficult breakthrough pain syndromes.[107][Level of evidence: I] An oral transmucosal fentanyl citrate compound for buccal administration has become available for this purpose.[108,109][Level of evidence: I] A double-blind, randomized, placebo-controlled study included 77 patients assigned to dose sequences of fentanyl buccal tablets. In addition, a 130-patient, randomized, double-blind, placebo-controlled trial using fentanyl sublingual spray was performed in opioid-tolerant patients. These studies demonstrated that both fentanyl buccal tablets and fentanyl sublingual spray were efficacious and safe in treating cancer-related breakthrough pain.[110,111][Level of evidence: I][112][Level of evidence: I] Other opioids such as morphine, hydromorphone, and oxycodone are not very lipophilic and therefore not suited for buccal or sublingual administration. In the home setting, opioids are sometimes administered buccally or sublingually with erratic absorption that is likely via the lower gastrointestinal tract.

IV administration provides a rapid onset of analgesia within 2 to 10 minutes. The duration of action after a bolus dose may be shorter than with other routes. This route may be useful if a patient cannot swallow and IV access is established.

The subcutaneous route is as effective as the IV route.[12,117][Level of evidence: I] In some situations, it may even be more convenient, especially if patients are being cared for at home or in a hospice. To facilitate administration via this route, a 25- or 27-gauge butterfly needle can be inserted subcutaneously and left in place for up to 7 days at a time. The anterior thighs, abdomen, upper arms, subclavicular area, and upper back are possible areas for needle insertion. The site should be monitored for signs of infection or irritation and should be changed if these are noted.

The bioavailability of parenterally administered opioids (morphine, hydromorphone, oxycodone, and codeine) is generally two to three times that of the oral route.[118][Level of evidence: II] The dose therefore needs to be halved or decreased by a third when switching from the oral to the subcutaneous and IV routes, respectively (refer to the Approximate Dose Equivalents for Opioid Analgesics table). Opioids administered parenterally may be given either intermittently (usually every 4 hours) or by a continuous infusion. With some exceptions, these two methods appear to be similarly effective.[119][Level of evidence: I]

Other routes

Some studies suggest that the use of inhaled opioids for the management of pain and cancer-related shortness of breath are, with some exceptions, not more effective than systemic administration.[120][Level of evidence: II];[121][Level of evidence: IV] Their absorption via this route is unpredictable.

The intramuscular administration of opioids is not recommended.

Patient-controlled analgesia

Patient-controlled analgesia (PCA) may be used to determine the opioid dose needs when initiating opioid therapy. Once the pain is well controlled, a regular opioid dose can be instituted on the basis of the PCA doses required. This method is contraindicated in patients with cognitive impairment or patients with significant psychological contribution to their pain experience.

Intraspinal

The intraspinal administration of opioids (epidural or intrathecal), especially when combined with a local anesthetic, can be helpful in a very small select group of patients with intractable pain. Use of the epidural or intrathecal route requires skill and expertise that may not be available in all settings. Table 4 presents the advantages and disadvantages of intraspinal administration. Intrathecal opioid therapy has been FDA approved since 1991, and the utility of an implantable drug delivery system (IDDS) to deliver spinal opioids has been compared with comprehensive medical management (CMM) (based on the Agency for Health Care Policy and Research 1994 cancer pain management guidelines) in a randomized trial. There were 202 patients enrolled in this unblinded study. Of the 101 patients randomized to the IDDS, 51 actually received this therapy. Sixteen of these patients (31%) had serious adverse effects. Patients using the IDDS experienced more than 20% reduction in both pain and opioid toxicity more often than the CMM group (P = .02). These data and further analysis in follow-up reports [122,123][Level of evidence: I] suggest that the use of an IDDS delivery system may offer benefit for some cancer patients. More research is needed to determine which subsets of patients will benefit the most from this device, and what the proper timing should be for a trial of intrathecal opioids.[124][Level of evidence I];[125][Level of evidence: II] An open-label study demonstrated that patients with refractory cancer pain experienced better pain relief, fewer opioid-associated side effects, and decreased systemic opioid use when managed with patient-activated intrathecal delivery of morphine via an implanted delivery system. The device was implanted in 119 patients. There were 7 serious adverse events related to the device and 55 serious adverse events related to the implant and delivery-system refill procedures. The FDA denied the application for market approval of this system.[80][Level of evidence: II]

Analgesic properties not demonstrated except for some instances of neuropathic pain.

Added sedation from anxiolytics may compromise neurologic assessment in patients receiving opioids by facilitating the development of delirium.

Sedative/hypnotic drugs alone

barbiturates, benzodiazepines

Analgesic properties not demonstrated.

Added sedation from sedative/hypnotic drugs limits opioid dosing and may facilitate the development of delirium.

Table 6. Routes of Administration To Be Avoided for Treatment of Cancer Pain

Routes of Administration

Rationale for Not Recommending

Intramuscular

Painful.

Absorption unreliable.

Should not be used in children or patients prone to develop dependent edema or patients with thrombocytopenia.

Transnasal

The only drug approved by the FDA for transnasal administration is butorphanol, an agonist-antagonist drug that generally is not recommended. (See opioid agonist-antagonists inTable 5for more information.)

Side effects of opioids

Clinicians should anticipate and monitor for side effects. The more common adverse effects include nausea, somnolence, and constipation. These should be discussed with patients before starting opioids. Somnolence and nausea are more often encountered with initiation of opioid treatment but tend to resolve within a few days. Clinicians who follow patients during long-term opioid treatment should watch for potential side effects and manage them as the need arises.

Constipation

Anticipate the constipating effects of analgesics. Opioids compromise gastrointestinal tract peristaltic function (a nearly universal side effect). Consequently, stool within the gut lumen becomes excessively dehydrated. The cornerstones of effective prophylaxis, therefore, are measures aimed at keeping the patient well hydrated to maintain well-hydrated stool. Unless there are existing alterations in bowel patterns, such as bowel obstruction or diarrhea, all patients using opioids should be started on a laxative bowel regimen and receive education for bowel management. Patients who do not adequately respond to an aggressive regimen with stool softeners may benefit from the addition of mild osmotic agents (e.g., 70% sorbitol solution, lactulose, milk of magnesia), polyethylene glycol, bulk-forming laxatives (e.g., psyllium) with appropriate orally administered hydration, or mild cathartic laxatives (e.g., senna). Stimulant cathartics (e.g., senna, bisacodyl) may be useful in severely constipated patients; however, they may be relatively ineffective in situations in which stool has become desiccated. Opioid-induced constipation is a frequent cause of chronic nausea and is observed in 40% to 70% of patients receiving opioids.[64][Level of evidence: I] It appears to be dose-related, is characterized by large variability in individuals, and is opioid-receptor mediated via both central and peripheral mechanisms. Opioids extend the gastrointestinal transit time and desiccate the intraluminal content.[126] Unlike nausea, complete tolerance to this effect does not generally develop, and most patients require laxative/stool-softener therapy for as long as they take opioids. A plain x-ray of the abdomen may be helpful in assessing the extent of fecal load.[127]

Initiating a regular laxative regimen emphasizes prevention of opioid-induced constipation. Recommendations regarding laxative treatment have been largely based on clinical experiences and observations. Combinations of a sennoside and a stool softener such as docusate are generally suggested.[128] Reports that fentanyl causes less constipation than oral morphine are interesting but need to be confirmed in further prospective studies.[129][Level of evidence: III];[63][Level of evidence: II] One study demonstrated decreased laxative use in patients on transdermal fentanyl as compared with patients receiving oral morphine treatment.[63] One meta-analysis has revealed a significant difference in favor of transdermal fentanyl for constipation, although this included only three randomized controlled clinical trials.[130] Whether this decrease in laxative usage is clinically significant, however, and whether the decrease relates to the route of administration instead of the opioid type need to be demonstrated. In a single small series, opioid switching of morphine to methadone resulted in a reduction in constipation.[131] Severe opioid-induced constipation may occur. At an extreme it may be present as a severe ileus and pseudo bowel obstruction.[132] As is the case with opioid-induced nausea and constipation, management relies on the use of gastrointestinal prokinetic agents. The use of orally administered opioid-antagonists such as naloxone is being studied.[133][Level of evidence: II];[134][Level of evidence: I] Although the oral bioavailability of these medications is very limited, opioid withdrawal syndromes have been noted when higher doses have been used. Methylnaltrexone, a quaternary derivative of naltrexone, is an opioid antagonist that does not cross the blood-brain barrier. Preliminary studies suggest that it may be effective when given subcutaneously in the management of opioid-associated constipation without causing opioid withdrawal.[135][Level of evidence: I];[136,137] (Refer to the PDQ summaries on Gastrointestinal Complications, Nausea and Vomiting, and Nutrition in Cancer Care for more information.)

Nausea and vomiting

Nausea and vomiting (emesis) occur in approximately one-third to two-thirds of patients taking opioids.[138][Level of evidence: I];[139,140] Nausea and vomiting are common complications of early exposure to opioids and usually disappear within the first week of treatment. Appropriate antiemetic coverage during the opioid-initiation phase is usually effective in limiting these adverse effects. Nausea alone does not represent an allergic reaction to the opioid. Occasionally, nausea may be experienced when an opioid dose is significantly increased. An antiemetic should be available on an as-needed basis to address this situation.

Three main mechanisms underlie opioid-related nausea and vomiting.[141] The predominant mechanism appears to be stimulation of the chemoreceptor trigger zone, where dopamine is the main neurotransmitter. Another mechanism is reduced gastrointestinal motility, including delayed gastric emptying. Nausea via increased vestibular sensitivity is uncommon.

Multiple antiemetic regimens have been proposed for the management of opioid-induced emesis, but prospective studies comparing one regimen over another are lacking.[141] Metoclopramide or domperidone are generally recommended as first-line agents because they improve gastrointestinal motility and are antidopaminergic.[141,142] Metoclopramide can be administered orally or subcutaneously at doses of 10 mg 4 times a day or every 4 hours, depending on the severity of the nausea. Rescue doses should also be ordered on an as-needed basis. Extrapyramidal-related adverse effects are a potential complication of these medications. The incidence of extrapyramidal reactions is low with domperidone, but this drug is not available in a parenteral formulation. The antihistamines act on the histamine receptors in the vomiting center and on vestibular afferents. They are generally reserved for cases in which vestibular sensitivity, often manifesting as motion-induced nausea, is suspected or for cases in which bowel obstruction precludes the use of gastrointestinal prokinetic agents. Haloperidol may also be used under the latter circumstances. The phenothiazines are an alternative group of antiemetics, but extrapyramidal and anticholinergic adverse effects may be dose-limiting. Chlorpromazine has modest antiemetic activity but a high incidence of sedation, postural hypotension, and anticholinergic adverse effects, whereas piperazine derivatives such as prochlorperazine are stronger antiemetics but cause more extrapyramidal side effects. Anticholinergic side effects also limit the use of anticholinergic agents such as hyoscine hydrobromide (scopolamine) in opioid-induced nausea, particularly in patients with advanced cancer. These patients seem to be more vulnerable to these adverse effects. The role of 5-HT3 -receptor antagonists such as ondansetron in ameliorating opioid-induced nausea is not clear.[143][Level of evidence: III]

There appear to be differences between individual patients in the extent to which different opioids cause nausea.[144] These differences form the basis for the strategy of switching from one opioid to another when a particular opioid produces persistent nausea.[145,146] Switching the route, specifically from the oral to the parenteral, has also been suggested, but the study supporting this strategy is small.[147][Level of evidence: II]

Nausea and vomiting can sometimes persist beyond the opioid-initiation phase or occur de novo in patients on long-term opioid treatment. Nausea and vomiting may become chronic in nature. The multicausal nature of the problem needs to be recognized because management is directed at identifying and addressing the various causes.[148] Constipation is a common contributing cause. Chronic nausea has been associated with the accumulation of active opioid metabolites.[93][Level of evidence: III] A number of strategies are suggested to manage chronic nausea, including switching the opioid or decreasing the dose when pain is well controlled. (Refer to the PDQ summary on Nausea and Vomiting for more information.)

Cognitive and other neurotoxic side effects of opioids

Opioid-related neurotoxicity may manifest as cognitive impairment, hallucinations, delirium, generalized myoclonus, hyperalgesia and/or allodynia. Patients who have renal impairment or who are taking higher doses of opioids are at greater risk of developing these side effects. The mechanisms underlying these side effects are unclear, but the opioid metabolites are implicated. When patients present with generalized pain of an unknown source and the opioid dose has been recently increased, hyperalgesia should be considered as a possible diagnosis.[149,150] The etiological contribution of opioids to cognitive impairment and delirium in the cancer patient is often difficult to determine. This is the case particularly in patients with advanced disease in which the baseline vulnerability is associated with multisystem impairment, and the concurrent administration of other psychotropic agents can complicate the assessment of etiology. Nonetheless, opioid-induced cognitive problems have been reported.[151,152] In addition to cognitive impairment within the context of delirium, other effects include myoclonus, hyperalgesia, perceptual disturbance, and seizures.[153] Although the remarkable characteristics, potential severity, and impact of delirium contribute to its dominance in the spectrum of opioid-related cognitive dysfunction, more subtle psychomotor and cognitive opioid effects have been described. Neuropsychological testing has been used to study these more-subtle effects in less-advanced cancer disease,[154][Level of evidence: II] chronic nonmalignant pain,[138][Level of evidence: I];[155][Level of evidence: II] and in healthy volunteers.[156][Level of evidence: I] Collectively, studies of neuropsychological testing have demonstrated somewhat mixed findings,[157] with some detecting opioid-associated impairment in certain aspects of psychomotor or cognitive function [155][Level of evidence: II] and others detecting minimal or no impairment.[138][Level of evidence: I];[154] Clinical experience and some studies suggest that patients become tolerant of the sedating effects that accompany either the initiation of opioid therapy or dose increases,[158][Level of evidence: II] thereby allowing patients who are otherwise physically able, and on stable opioid doses, to safely engage in activities such as driving.[154,159]

Decreased brain cholinergic activity is recognized as one of the potential underlying pathophysiological mechanisms of delirium.[160,161][Level of evidence: II] In the case of meperidine, the anticholinergic activity associated with its active metabolite normeperidine is suspected to be the basis of the cognitive impairment and delirium occurring in association with this opioid.[162,163] Other opioid metabolites have been studied in relation to the generation of neuroexcitatory states in animal laboratory models and delirium in human subjects. A series of animal studies have demonstrated neuroexcitatory states in association with morphine metabolites, morphine-3-glucuronide (M-3-G) [164] and normorphine-3-glucuronide,[165] and the hydromorphone metabolite, hydromorphone-3-glucuronide.[166][Level of evidence: II] In a hospice study of 36 patients with advanced cancer receiving morphine, both M-3-G and morphine-6-glucuronide (M-6-G) levels were studied in relation to the development of side effects, which included nausea and vomiting in 10 patients and cognitive impairment in 9 patients.[167][Level of evidence: II] Creatinine levels, and plasma levels of M-3-G, M-6-G, and dose-corrected M-3-G and M-6-G, were higher in the 19 patients with side effects, suggesting that the elevation of morphine metabolites in association with renal impairment was associated with opioid toxicity, including cognitive impairment. Evidence is extensive demonstrating elevation of opioid-metabolite levels in the setting of renal impairment,[91,98,167][Level of evidence: II];[168,169] and some studies have noted an association with features of neurotoxicity, including cognitive impairment.[152,167][Level of evidence: II] An accumulation of opioid metabolites possibly also occurs during dehydration, which was suggested as a contributory factor in a prospective study of predominantly opioid-related delirium.[170][Level of evidence: II] Switching to another opioid is one strategy for abating the side effects in cases in which accumulation of active metabolites is considered responsible for side effects such as generalized myoclonus, sedation, confusion, or chronic nausea.[26]

Managing cognitive and other neurotoxic effects of opioids

The general management approach to opioid-induced delirium requires a multidimensional assessment to determine the presence of other potentially treatable contributory factors such as dehydration, other centrally acting medications, sepsis, and hypercalcemia.[151,170,171] Clinical experience suggests that the presence of tactile hallucinations and myoclonus,[84] although not exclusively associated with opioid toxicity, raise the suspicion of this cause. A careful assessment can also identify prognostic factors associated with greater difficulty in achieving pain control, the need for higher opioid doses, and consequently greater risk of opioid-induced delirium. (Refer to the PDQ summary on Delirium for more information.) These factors include neuropathic pain, incidental pain, tolerance, somatization of psychological distress, and a positive history of drug or alcohol abuse.[172][Level of evidence: II]

In addition to searching for underlying reversible causes of delirium, the symptomatic management of delirium requires the addition of a neuroleptic agent to control agitation and perceptual or delusional disturbance. Haloperidol is regarded as the drug of choice in this context,[173] and methotrimeprazine and chlorpromazine are considered useful alternatives,[174][Level of evidence: I];[175][Level of evidence: IV] especially when a greater level of sedation is required. Midazolam, a sedating and short-acting benzodiazepine given by continuous infusion, is sometimes necessary, especially in the case of nonreversible delirium.[176][Level of evidence: III] Typical anxiolytics, including lorazepam, can be used to manage comorbid anxiety; however, they may contribute to the occurrence of delirium, so they should be used sparingly, if at all. Early data suggest that some atypical antipsychotics may be beneficial in improving pain control and decreasing opioid requirements in the cancer patient with mild cognitive impairment and/or anxiety. It is unclear whether this benefit is due to a primary effect or to its secondary impact on cognitive impairment and/or anxiety.[177][Level of evidence: II]

The specific management approach to opioid-induced cognitive and other neurotoxic side effects involves either a dose reduction, a change in route, or an opioid switch.[178][Level of evidence: II] If the pain is well controlled, and the cognitive and neurotoxic side effects are not severe, modest opioid dose reduction may be effective. The rationale for switching opioids, commonly referred to as opioid switching, is that a more favorable balance between analgesia and side effects can be achieved, often with a lower dose than that predicted by the conventional analgesic table.[85,151,179] This can reflect incomplete cross-tolerance among opioids in relation to analgesic and other effects.[180] It is also possible that switching to a new opioid could allow for the elimination of potentially toxic opioid metabolites.[181][Level of evidence: III];[151,182] Reduction in opioid dose in the context of an opioid-induced delirium has not been systematically evaluated but is also likely to have beneficial results. Although there is growing evidence to suggest a beneficial role for opioid switching,[146][Level of evidence: II];[181,183] controversy persists over the relative value of opioid switching versus dose reduction.[83]

Cognitive benefit has been reported with the use of methylphenidate in patients receiving a continuous infusion of opioids for cancer pain.[184][Level of evidence: I] The psychostimulant benefit is likely to relate to mitigation of sedation associated with upward dose titration of opioid.[185][Level of evidence: II] Although psychostimulants have been advocated for hypoactive delirium,[186][Level of evidence: IV] any evidence of perceptual or delusional disturbance is considered a contraindication. An open-label study of donepezil, a long-acting selective acetylcholinesterase inhibitor, suggests that it relieves opioid-associated fatigue and sedation in patients who are receiving opioids for cancer pain.[187][Level of evidence: II]

Respiratory depression

Patients receiving long-term opioid therapy generally develop tolerance to the respiratory-depressant effects of these agents. However, concerns about respiratory depression with opioid use remain prevalent among clinicians and patients. Clinicians experienced in end-of-life care recognize that such concerns are generally exaggerated, though empirical research in the area is sparse. One observational study of 30 patients that evaluated the effect of parenteral opioid titration for the control of acute exacerbation of cancer pain showed no association between parenteral opioid titration and hypoventilation at pain control, as measured by change in end-tidal CO2 respiratory rate or oxygen saturation.[188]

When indicated for reversal of opioid-induced respiratory depression, naloxone titrated in small increments or as an infusion should be administered to improve respiratory function without reversing analgesia. The patient should be monitored carefully until the episode of respiratory depression resolves. The opioid antagonists have a short half-life and may have to be given repeatedly until the agonist drug is sufficiently cleared.[189]

Subacute overdose

Perhaps more common than acute respiratory depression, subacute overdose may manifest as slowly progressive (hours to days) somnolence and respiratory depression. Before analgesic doses are reduced, advancing disease must be considered, especially in the dying patient. Generally, withholding one or two doses of an opioid analgesic is adequate to assess whether mental and respiratory depression are opioid related. If symptoms resolve after temporary opioid withdrawal, reduce the scheduled opioid dosage by 25%. If symptoms do not abate, but the patient complains of or exhibits signs of increased pain, or if symptoms referable to opioid withdrawal occur, consider alternative causes for CNS depression and reinstate analgesic treatment. Ongoing assessment is essential to maintain adequate pain relief.

Effects of opioids on sexual function

Reduced libido is a well-known phenomenon for those using heroin or those in a methadone maintenance program; however, clinicians prescribing opioids for pain poorly understand this effect. Early case studies of persons using heroin or methadone described diminished libido, sexual dysfunction, reduced testosterone levels in men, and amenorrhea in women.[190,191,192,193][Level of evidence: II];[194,195] These effects resolve after the opioid has been discontinued. Other case reports of patients receiving opioids for relief of chronic pain suggest these same findings.[196,197][Level of evidence: III] The long-term effects of reduced testosterone and amenorrhea are not well known. Sexuality is an essential component of quality of life in many patients, including patients with advanced disease.[198][Level of evidence: III] Patients should be assessed for changes in libido and sexual dysfunction. If these changes are distressing to the patient, serum testosterone levels may be obtained. Should the patient seek improvement in libido and performance, treatment is often empirical, keeping in mind that there are many potential causes of changes in sexual function. Treatment includes using nonopioids for pain, adding adjuvant analgesics in the hope the opioid dose may be reduced, or replacing testosterone through injections or a patch (if not contraindicated). More research is needed to understand the relationship between opioids and sexual function, as well as the most effective treatment strategies. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information.)

Adjuvant drugs are valuable during all phases of pain management to enhance analgesic efficacy, treat concurrent symptoms, and provide independent analgesia for specific types of pain.[199][Level of evidence: IV] Adverse drug reactions are common, however, and there are wide interindividual and ethnic differences in drug metabolism.[200][Level of evidence: IV] A survey on symptom severity and management in 593 cancer patients treated for an average of 51 days reported that during this time, anticonvulsants were used in 11.8% of patients, antidepressants in 16%, corticosteroids in 28%, and bisphosphonates in 7.3%.[201][Level of evidence: III] Patients with advanced cancer on palliative medicine services are reported to receive on average five medications for symptom relief, and as a result are at high risk of drug interactions.[200] A further note of caution appears in another study that questioned the concept of opioid-sparing effects of co-analgesics.[202][Level of evidence: III] Nevertheless, adjuvant analgesics have been extensively studied and reviewed in noncancer settings and are generally endorsed as an important intervention in the provision of adequate pain management (see Table 7).[203,204,205,206][Level of evidence: IV] Few trials compare adjuvant analgesics in the cancer setting. Not all analgesic agents have been shown to provide clinical benefit when used in conjunction with opioids. In a dose escalation, double-blind, randomized placebo-controlled phase III trial of ketamine in patients with uncontrolled pain on opioids, delivered subcutaneously over 3 to 5 days, versus placebo, there was no difference noted in pain response between arms. There was almost twice the incidence of adverse effects in the ketamine group than was in the placebo arm.[207][Level of evidence: I]

Refer to theNMDA Receptor Antagonistssection of this summary for more information.

Antidepressants

The analgesic benefits of tricyclic antidepressants have been well established and are generally considered first-line therapy for many neuropathic pain syndromes.[203,204,205,206,234][Level of evidence: IV] Supporting evidence is strong for amitriptyline and desipramine, and there is endorsement of other newer antidepressants such as maprotiline and paroxetine. Patients with neuropathic pain characterized by continuous dysesthesias are generally believed to be the most likely to benefit from antidepressant management; however, a randomized placebo-controlled study of amitriptyline for neuropathic pain in cancer patients found only slight analgesic benefit with significantly worse adverse effects.[209][Level of evidence: I]

The most common side effects of tricyclic antidepressants are the following:

Constipation.

Dry mouth.

Blurred vision.

Cognitive changes.

Tachycardia.

Urinary retention.

Caution has also been advised in treating patients with cardiac disease, and an electrocardiogram is sometimes recommended as a prudent measure. A slow upward titration is suggested as a good way to avoid side effects.[216][Level of evidence: I]

Anticonvulsants

The group of commonly used anticonvulsants as adjuvant analgesics for neuropathic pain includes carbamazepine, valproate, phenytoin, and clonazepam.[203,204,205,206,234][Level of evidence: IV]

Clinical experience with carbamazepine is extensive, but use of this drug is limited in the cancer population because of concern that it causes bone marrow suppression, in particular leukopenia. Other common adverse effects include nystagmus, dizziness, diplopia, cognitive impairment, and mood and sleep disturbance.

Dosing guidelines for phenytoin are similar to those for the treatment for seizures.[203] This drug can be administered using a loading dose, which may be particularly useful in patients with severe pain.

Gabapentin is increasingly reported as useful for the management of neuropathic pain associated with cancer and its treatment.[221][Level of evidence: I];[222,235][Level of evidence: II];[236][Level of evidence: III];[237,238][Level of evidence: IV] Commonly reported side effects include somnolence, dizziness, ataxia, and fatigue.[206,236] One randomized open-label trial of gabapentin combined with an opioid (n = 38) versus an opioid alone (n = 37) for the management of neuropathic cancer pain suggests that the combination group achieved better relief than those receiving opioid monotherapy.[239][Level of evidence: I]

Clonazepam is an anticonvulsant from the benzodiazepine class and is commonly used for treating lancinating or paroxysmal neuropathic pain.[203] The patient must be monitored carefully for drowsiness and cognitive impairment.

Local anesthetics

The use of mexiletine has been described for chronic neuropathic pain.[203,204,206] Side effects are reported as common and include gastrointestinal toxicity, in particular nausea, and CNS side effects such as dizziness. Patients with a history of cardiac disease and those on higher doses are at increased risk of adverse effects, and it is recommended that they receive appropriate cardiac evaluation, including an electrocardiogram.

Corticosteroids

These drugs have achieved wide acceptance in the management of patients with cancer pain. They are indicated as adjuvant analgesics for cancer pain of bone, visceral, and neuropathic origin. Adverse effects include neuropsychiatric syndromes, gastrointestinal disturbances, proximal myopathy, hyperglycemia, aseptic necrosis, capillary fragility, and immunosuppression. The risk of adverse effects increases with the duration of use. As a result, use is often restricted to patients with a limited life expectancy; in addition, once effective pain control is obtained, it is commonly recommended that the dose be tapered as much as possible. Dosage recommendations vary from a trial of low-dose therapy such as dexamethasone 1 to 2 mg or prednisone 5 to 10 mg once or twice daily,[203] to a starting dose of dexamethasone 10 mg twice daily with subsequent tapering to the minimal effective dose.[240]

Another suggested use of corticosteroids is in high doses for short periods in patients with severe pain. This empirical approach recommends a regime of a single bolus of dexamethasone 100 mg IV followed by a small amount given 4 times per day and then tapered over the next few weeks.[203]

Although there is widespread acceptance of steroid therapy, mostly via the oral route but also subcutaneously and intravenously, data remain inadequate for definitive conclusions regarding efficacy and dosing guidelines.[241][Level of evidence: I];[203];[205,206,240,242,243,244,245][Level of evidence: IV]

Bisphosphonates

These drugs have been recommended for the management of bone pain as well as the prevention of skeletal complications in patients with metastatic bone disease.[246][Level of evidence: II];[203];[204,205,206,247,248,249][Level of evidence: IV] Their use in a study of breast cancer patients resulted in improved quality of life compared with that of patients not using bisphosphonates.[250][Level of evidence: I] The bisphosphonates most frequently used are clodronate, pamidronate,[251] and zoledronic acid.[252][Level of evidence: I]

Clodronate can be given orally or intravenously. Dosage recommendations are oral clodronate, 1,600 mg/d; or IV clodronate, 600 to 1,500 mg every 2 to 3 weeks. Clodronate is not available in the United States.

Pamidronate has been recommended in the dose range of 60 to 90 mg IV over 2 hours every 3 to 4 weeks; however, pooled results from two multicenter, double-blind, randomized, placebo-controlled trials (n = 350) using pamidronate (90 mg every 3 weeks) failed to demonstrate a benefit for bone pain.[253][Level of evidence: I]

Zoledronic acid is a potent bisphosphonate that can be given as an IV bolus over 15 to 30 minutes in the dose range of 4 to 8 mg; however, the 8-mg dose has been associated with deterioration of renal function.[254,255,256,257][Level of evidence: I] The few studies to date suggest administration at 3- to 4-week intervals.[258][Level of evidence: IV]

Ibandronate can be given orally or intravenously. Dosing recommendations are 50 mg orally daily or 6 mg intravenously every 3 to 4 weeks.[259][Level of evidence: I]

Denosumab is a monoclonal antibody against the receptor activator of nuclear factor-kappa B ligand (RANKL), which is a form of the tumor necrosis factor superfamily. RANKL inhibition prevents osteoclast development and activation, resulting in decreased bone resorption, increased bone density, and reduction in the risk of fractures.[260]

The FDA has highlighted the possibility of severe and sometimes incapacitating bone, joint, and/or muscle pain in patients who are taking bisphosphonates. The musculoskeletal pain may occur within days, months, or years after starting treatment with a bisphosphonate. This pain contrasts with the acute-phase response characterized by fever, chills, bone pain, myalgias, and arthralgias that may sometimes accompany initial administration of intravenous bisphosphonates. The FDA recommends that bisphosphonates be considered a possible cause of severe musculoskeletal pain in patients who present with these symptoms, and health care professionals should consider temporary or permanent discontinuation of the drug. The risk factors and the incidence of the association of this musculoskeletal pain with bisphosphonates remain unknown.[261]

The use of bisphosphonates carries a risk of developing bisphosphonate-associated osteonecrosis (BON). (Refer to the Oral Toxicities Not Related to Chemotherapy or Radiation Therapy section in the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation for more information.)

Miscellaneous

Baclofen

This drug is generally used for spasticity but may also be used for the treatment of neuropathic pain.[203,204,206][Level of evidence: IV] Side effects include drowsiness, dizziness, ataxia, confusion, and nausea and vomiting.

Calcitonin

Although the mechanism by which calcitonin produces analgesia is unknown, historically it has been recommended for the treatment of both bone and neuropathic pain.[203,204,206,247,248] However, a systematic review of randomized double-blind clinical trials assessing the efficacy of calcitonin for control of metastatic bone pain does not support its use.[262][Level of evidence: IV] Because only two of these studies were evaluated as well designed, further research is necessary. The utility of calcitonin for bone pain is unclear.

Clonidine

This traditional antihypertensive can be given via the oral, epidural, or transdermal route and has been recommended as a trial for the management of neuropathic pain. Reported side effects include dry mouth, dizziness and hypotension, sedation, and constipation.[203,204,206][Level of evidence: IV] The maximum recommended dose is 2.4 mg/d.

Psychostimulants

Psychostimulants such as dextroamphetamine, methylphenidate, and modafinil may enhance the analgesic effects of opioids.[184][Level of evidence: I];[185][Level of evidence: II];[205][Level of evidence: IV] They may also be used to diminish opioid-induced sedation when reducing the dose is not possible.

NMDA Receptor Antagonists

There is increasing evidence for the importance of NMDA receptors and the possibility that NMDA antagonists may have a role in refractory cancer pain management.[203,263][Level of evidence: III] Ketamine in subanesthetic doses has been used in this setting.[264][Level of evidence: II] The severe psychomimetic adverse effects associated with this treatment, including vivid hallucinations, limit widespread use of ketamine. Coadministration of a neuroleptic or benzodiazepine is recommended to limit the emergence of these effects. Ketamine is generally given subcutaneously at a low starting dose such as 0.1 mg per kg of body weight per hour, with a gradual escalation. Oral ketamine may be a more potent analgesic and have a more favorable side-effect profile than parenteral ketamine.[249][Level of evidence: IV] One study suggests short-duration therapy of a continuous subcutaneous infusion of ketamine over 3 to 5 days. The initial dose is 100 mg/d; if pain control is inadequate, the dose is escalated to 300 mg/d and then to a maximum dose of 500 mg/d. Treatment is continued for 3 days at either the lowest effective dose or 500 mg/d and then discontinued.[263] A systematic review of the benefits and harms of ketamine in managing cancer pain revealed a general lack of studies and small subject numbers,[265,266][Level of evidence: IV] precluding a definitive conclusion on benefits and harms.

Methadone, particularly the racemic mixture, appears to have significant NMDA-antagonist properties.[267] The d-isomer blocks the NMDA receptor and as a result may yield independent analgesic effects and perhaps reverse some analgesic tolerance to the opioid.[268][Level of evidence: II] This may explain the often-unanticipated high potency of methadone.

Dextromethorphan (DM), a commonly prescribed antitussive, may also have NMDA-blocking properties.[268][Level of evidence: II] The clinical significance of this effect, however, is unclear and studies have not been able to determine at what dose these effects may manifest. Oral DM in doses of 60 or 90 mg given preoperatively and postoperatively has been shown to reduce pain intensity and opioid use after orthopedic oncology surgery.[269,270][Level of evidence: I] A randomized, double-blind, placebo-controlled study of 65 patients evaluated the efficacy and safety of DM or placebo with slow-release morphine. The dose of DM was 60 mg 4 times daily, increased after 7 days to 120 mg 4 times daily if tolerated. While the DM group showed somewhat more improvement than the placebo group, the differences were not significant; furthermore, the DM group experienced more toxic effects, particularly dizziness.[271][Level of evidence: I] The authors concluded that DM does not enhance opioid analgesia or modulate opioid tolerance enough in cancer patients to warrant continued use.

Octreotide

Data from a case series of 16 patients with symptomatic hepatic metastases from a variety of nonneuroendocrine primary sites suggest that octreotide palliates pain and improves a variety of quality-of-life indices as measured by the EORTC QLQ-C30 questionnaire.[272][Level of evidence: II]

Under Investigation

Tetrodotoxin

A randomized, placebo-controlled study of subcutaneous tetrodotoxin was carried out on 77 cancer patients across 22 centers in Canada. While results did not achieve statistical significance, there was a trend toward improved pain control. This drug remains experimental and is not commercially available.[273][Level of evidence: I]

Cannabinoids

Cannabis contains more than 60 cannabinoids and has been proposed as a potentially useful treatment for cancer-related pain. A multicenter, double-blind, randomized, placebo-controlled study included 177 cancer patients in a trial of an endocannabinoid system modulator. Positive analgesic effects were observed and merit further study.[274][Level of evidence: I] Another randomized, double-blind, placebo-controlled, graded-dose study was conducted in patients with advanced cancer who had opioid-refractory pain.[275] Patients received either placebo or nabiximols (a cannabinoid formulation) intranasally; nabiximols consisted of 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD) per 100-μL spray. Patients were randomly assigned to low-dose (2.7–10.8 mg THC and 2.5–10 mg CBD), medium-dose (16.2–27 mg THC and 15–25 mg CBD), or high-dose (29.7–43.2 mg THC and 27.5–40 mg CBD) levels and were assigned to placebo or active drug within each dose group. A total of 263 patients completed the study, which measured average pain, worst pain, sleep disturbance, and other quality-of-life issues. There was no significant difference in the 30% responder rate, which was the primary analysis. However, in a continuous responder analysis evaluating average daily pain from baseline to end of study, there was a statistically significant greater analgesia for nabiximols (P < .05) versus placebo overall, specifically in the low- and medium-dose groups. Only the high-dose group compared unfavorably with placebo because of adverse events. The authors concluded that nabiximols may be a useful adjunct in treating opioid-refractory pain.[275]

Current Clinical Trials

Check NCI's list of cancer clinical trials for U.S. supportive and palliative care trials about pain that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Bartlett SE, Cramond T, Smith MT: The excitatory effects of morphine-3-glucuronide are attenuated by LY274614, a competitive NMDA receptor antagonist, and by midazolam, an agonist at the benzodiazepine site on the GABAA receptor complex. Life Sci 54 (10): 687-94, 1994.

Lavand'homme PM, Eisenach JC: Perioperative administration of the alpha2-adrenoceptor agonist clonidine at the site of nerve injury reduces the development of mechanical hypersensitivity and modulates local cytokine expression. Pain 105 (1-2): 247-54, 2003.

Palliative Interventions

Radiation Therapy

Radiation therapy (RT) has been established as an effective treatment for pain caused by bony metastases. Local, half-body, or whole-body RT enhances the effectiveness of analgesic drugs and other noninvasive therapies by directly affecting the cause of pain (i.e., reducing primary and metastatic tumor bulk).[1][Level of evidence: I] RT reduces pain and its interference with function among ambulatory cancer patients with symptomatic bone metastases.[2]

External-beam radiation for bone metastases

External-beam radiation therapy (EBRT) produces significant reduction in bone pain in 50% to 80% of patients, with complete pain relief in 30% to 50% of patients.[3] Dose fractionation schedules utilized for painful bone metastases vary considerably. Common fractionation schemes include 30 Gy in ten fractions, 24 Gy in six fractions, 20 Gy in five fractions, and 8 Gy in one fraction. Single- or multiple-fraction regimens of EBRT are equally effective when RT is administered for pain relief; however, re-treatment is needed more frequently after single-fraction RT.[4][Level of evidence: I];[2,5][Level of evidence: II] Fractionated RT courses have been associated with a need for re-treatment in 0% to 12% of patients versus a need for re-treatment in 11% to 25% of patients after a single fraction.[3,4,6,7,8,9][Level of evidence: I];[5][Level of evidence: II]

The dose and fractionation schedule must achieve a balance between the amount of RT required to kill tumor cells and the amount that would adversely affect normal cells or allow repair of damaged tissue. Data from several prospective randomized trials have failed to show any increased rates of long-term toxicity with single-fraction palliative RT compared with multiple-fraction therapy. In addition to pain control considerations, impact on the patient and caregiver related to the number of treatments delivered must be considered, with many patients finding increased convenience with single-fraction treatment. Another consideration is treatment cost, with single-dose fractionation regimens being less costly because of the smaller number of RT treatments delivered.

Stereotactic body RT (SBRT) is used to treat bone metastases by delivering large doses of RT in a highly conformal manner. Most commonly used to treat spinal metastatic disease, SBRT delivers large doses with a steep dose gradient, thereby potentially sparing adjacent neural structures. Most published data on SBRT have come from single-institution, retrospective studies. The complexities of target delineation, total dose, and fractionation have yet to be fully defined. SBRT may also be used when re-treatment is required in previously irradiated areas. Data regarding RT dose or patient selection for the treatment of recurrent, painful spinal bony metastases with SBRT are not yet definitive.[10]

Pain flare, defined as an increase in pain after palliative RT, can occur, although the incidence has not been well documented. A relatively small, prospective, randomized, controlled trial comparing 8 Gy in one fraction with 20 Gy in five fractions reported pain flare in 15 of 44 patients (34%) for a median duration of 3 days. The flare occurred in 10 of 23 patients (44%) in the 8-Gy group and in 5 of 21 patients (24%) in the 20-Gy group.[11][Level of evidence: I] A multicenter study included three outpatient clinics and 111 patients to determine the incidence of pain flare after palliative RT. Pain flare was defined in this study as an increase in pain severity before achieving pain relief as distinguished from progression of pain by requiring the worst pain score and analgesic intake return to baseline levels after the increase/flare. Most patients received 8 Gy in one fraction (64%) or 20 Gy in five fractions (25%). The overall pain flare incidence was 40% (39% with 8 Gy and 41% with multiple fractions).[12][Level of evidence: II]

The use of RT with bisphosphonates has been evaluated in several prospective trials. The combination of zoledronic acid with either higher-dose palliative RT (30 Gy in ten fractions) or lower-dose RT (15 Gy in five fractions) for the treatment of single or multiple osteolytic or osteoblastic painful bony metastases in breast cancer patients was evaluated in a phase IV, randomized, controlled trial.[13] Zoledronic acid, 4 mg, was given every 28 days starting with RT. There was no difference in analgesic or pain scores between the two regimens. However, it has not been shown that the combination of these agents with RT is superior to RT alone for pain relief. Additional prospective trials are needed.

Radiopharmaceuticals

Radiopharmaceuticals are also utilized in the palliation of painful bony metastases. Single intravenous injections of beta-emitting agents such as iodine 131, phosphorus-32-orthophosphate, and strontium 89 and newer agents such as rhenium 186 and samarium 153 can relieve pain in widespread bony metastases.[14,15][Level of evidence: II];[16,17] Response rates range from 20% to 85%, depending on the agent used.

These agents have most commonly been used to treat osteoblastic metastases when there are several symptomatic sites and/or when the number of sites exceeds reasonable treatment with EBRT. Small-volume osteolytic metastases may respond to radiopharmaceuticals, but large-volume osteolytic disease usually does not respond. In patients with inadequate pain relief, studies have demonstrated that approximately one-half of patients treated with radiopharmaceuticals respond to a second treatment. A prospective, multicenter, open-label trial of samarium suggested that multiple doses (i.e., more than two doses) may be administered to patients with advanced cancer and painful bone metastases with repeated benefit and adequate safety if there was an initial response to the initial samarium dose.[18][Level of evidence: II]

Available data do not suggest that these radiopharmaceuticals eliminate the need for palliative EBRT.[10] Limited studies compare the effectiveness of one radiopharmaceutical with another. In a small randomized trial comparing strontium with samarium in patients with painful bony metastases, there was no statistically significant difference in the degree of analgesia seen. Toxicity, primarily hematologic, was likewise similar.[19]

Radiofrequency ablation

Radiofrequency ablation (RFA) is a relatively new method for treating symptomatic bony metastasis. Through the use of electromagnetic energy, RFA induces thermal energy that damages tissue around the inserted electrode. The destruction of tissue depends on the temperature achieved and the duration of heating. With the use of image guidance, the goal of RFA is to maintain temperatures between 55°C and 100°C for 4 to 6 minutes to achieve cell kill. Because of slow thermal conduction through tissue, treatment time may increase up to 30 minutes. Preliminary results suggest that RFA may achieve palliation in patients with painful bony metastases.[20,21,22,23];[24][Level of evidence: III]

In a nonconsecutive 27-month period, 43 patients underwent RFA. Of the 43 patients, 41 (95%) experienced a decrease in worst pain (at least 2 points on an 11-point scale) that continued for up to 24 hours. After peaking at week 1, the morphine-equivalent daily dose decreased significantly at weeks 8 and 12 before rising again at week 24. Three patients experienced adverse events that included a second-degree skin burn at the grounding pad site, transient bladder and bowel incontinence after treatment of a sacral lesion, and an acetabular fracture 6 weeks after RFA of a pelvic lesion.[23] Other uncontrolled case reports confirm these findings. Further study is needed to determine potential risks and benefits.

Invasive Palliative Interventions

Less-invasive analgesic approaches should precede invasive palliative approaches; however, for a minority of patients in whom behavioral, physical, and drug therapy do not alleviate pain, invasive therapies are useful.

Nerve blocks

Control of otherwise intractable pain can be achieved by the application of a local anesthetic or neurolytic agent. Nerve blocks are performed for several reasons:

Prognostic: To predict the outcome of long-lasting interventions (e.g., infusions, neurolysis, and rhizotomy).

Preemptive: To prevent procedure-related pain.

A single injection of a nondestructive agent such as lidocaine or bupivacaine, alone or in combination with an anti-inflammatory corticosteroid for a longer-lasting effect, can provide local relief from nerve or root compression.[25] Placement of an infusion catheter at a sympathetic ganglion extends the sympathetic blockade from hours to days or weeks. Destructive agents such as ethanol or phenol can be used to effect neurolysis at sites identified by local anesthesia as appropriate for permanent pain relief and may also be used to cause destruction of central nervous system structures. The efficacy of neurolytic sympathetic blocks may vary depending on the underlying pain mechanisms involved. For patients with multiple pain mechanisms, neurolytic sympathetic blocks may serve as adjuvant techniques to analgesic medications.[26][Level of evidence: II]

Neurologic interventions

Neurosurgery can be performed to implant devices that deliver drugs or electrically stimulate neural structures. Surgical ablation of pain pathways should, like neurolytic blockade, be reserved for situations in which other therapies are ineffective or poorly tolerated. In general, the choice of neurosurgical procedure is based on location and type of pain (somatic, visceral, deafferentation), the patient's general condition and life expectancy, and the expertise and follow-up available.

Management of procedural pain

Many diagnostic and therapeutic procedures are painful to patients. Anticipated procedure-related pain should be treated prophylactically, integrating pharmacologic and nonpharmacologic interventions in a complementary style.

Local anesthetics and short-acting opioids can be used to manage procedure-related pain, when adequate time is allotted for the drug to achieve full therapeutic effect. Anxiolytics and sedatives may be used to reduce anxiety or to produce sedation.

Cognitive-behavioral interventions such as imagery or relaxation may be useful in managing procedure-related pain and anxiety. (Refer to the Cognitive-Behavioral Interventions section of this summary for examples of relaxation exercises.) Patients generally tolerate procedures better when they are informed about what to expect.

Offering the option for a relative or friend to accompany the patient for support can be useful.

Patients should be encouraged to remain active and participate in self-care when possible. Noninvasive physical, integrative (complementary/alternative therapies), cognitive-behavioral, and psychosocial modalities are typically used in conjunction with pharmacotherapy to manage pain during all phases of treatment. These interventions have the potential to enhance pain control directly but also indirectly, by increasing a patient's sense of control over events. The effectiveness of these modalities depends on the patient's participation and communication of which methods best alleviate pain. Minority patients of various ethnicities have been noted to experience worse control of their pain, which may result from miscommunication issues within the medical setting. In a post hoc analysis of a small trial, minority (various ethnicities) (n = 15) and white (n = 52) cancer patients were randomly assigned either to a 20-minute individualized education-and-coaching session regarding pain management (including how to discuss their concerns with their physician) or to usual care. At baseline, minority patients reported significantly more pain than white patients (6.0 vs. 5.0), whereas at follow-up, disparities had been eliminated in the intervention group (4.0 vs. 4.3) but remained in the control group (6.4 vs. 4.7).[1][Level of evidence: I]

Physical Modalities

Generalized weakness, deconditioning, and musculoskeletal pain associated with cancer diagnosis and therapy may be treated by:

Heat

Avoid burns by wrapping the heat source (e.g., hot pack or heating pad) in a towel. A timing device is useful to prevent burns from an electrical heating pad. The use of heat on recently irradiated tissue is contraindicated, and diathermy and ultrasound are not recommended for use over tumor sites.

Cold

Apply flexible ice packs that conform to body contours for periods not to exceed 15 minutes. Cold treatment reduces swelling and may provide longer-lasting relief than heat but should be used cautiously in patients with peripheral vascular disease and on tissue damaged by radiation therapy.

Exercise

Exercise strengthens weak muscles, mobilizes stiff joints, helps restore coordination and balance, and provides cardiovascular conditioning. Therapists and trained family or other caregivers can assist the functionally limited patient with range-of-motion exercises to help preserve strength and joint function. During episodes of acute pain, exercise should be limited to self-administered range-of-motion. Weight-bearing exercise should be avoided when bone fracture is likely.

Repositioning

Reposition the immobilized patient frequently to maintain correct body alignment, to prevent or alleviate pain, and to prevent pressure ulcers.

Immobilization

Use restriction of movement to manage acute pain or to stabilize fractures or otherwise compromised limbs or joints. Use adjustable elastic or thermoplastic braces to help maintain correct body alignment. Keep joints in positions of maximal function rather than maximal range. Avoid prolonged immobilization.

Stimulation Techniques

Transcutaneous Electrical Nerve Stimulation (TENS): Controlled low-voltage electrical stimulation applied to large myelinated peripheral nerve fibers via cutaneous electrodes to inhibit pain transmission. Patients with mild-to-moderate pain may benefit from a trial of TENS to see if it is effective in reducing the pain. TENS is a low-risk intervention. A small crossover study (N = 41) found that 72% of users rated TENS as effective or very effective, compared to those using the comparison intervention (27%) or placebo intervention (36%). Furthermore, a clinically meaningful number of participants was still using the TENS a year later (n = 10), in contrast to the other two conditions (combined n = 5). All three treatment arms were well tolerated, but there is no conclusive evidence demonstrating any benefit from TENS or transcutaneous spinal electroanalgesia (TSE) over placebo in this cancer pain population.[2][Level of evidence: I]

Integrative Modalities

Massage, Pressure, and Vibration

Physical stimulation techniques have direct mechanical effects on tissues and enhance relaxation when applied gently. Tumor masses should not be aggressively manipulated.

Massage therapy is an integrative modality that has been investigated as an adjunct to supportive care interventions in managing cancer-related pain. Preclinical and clinical trials have found that massage reduces pain by reducing cortisol levels, increasing serotonin and dopamine levels, stimulating the release of endorphins, and stimulating blood and lymphatic circulation. Massage may enhance the effects of analgesic medications and decrease inflammation and edema. There is a large body of evidence supporting the role of massage in reducing pain associated with muscle-related conditions such as muscle spasms and tension.[3,4,5,6] Massage may also play a role in the management of procedural pain.

In one of the largest randomized trials, 380 adults with advanced cancer received six sessions of either massage therapy or touch therapy for 30 minutes over a 2-week period.[3] While immediate improvements from massage therapy were significantly greater than those from touch therapy, the benefits were not sustained, according to the Brief Pain Inventory. However, a large number of patients were not included in the assessments of immediate outcomes or sustained outcomes. Data collectors were also not blinded to the study arm, which may have led to overreporting the effects of massage therapy or touch therapy.

A number of reviews exploring the role of massage in the management of cancer pain or other areas of supportive care have been published. In a Cochrane review of the role of massage therapy with or without aromatherapy as a component of supportive care,[7] three studies found a reduction in pain following intervention and reported reductions of 30% to 39% in pain scores after massage therapy, compared to usual care. Another study reported on the role of massage within the context of supportive care in cancer, highlighted pain, and concluded that evidence is encouraging but effect sizes are small.[5] Additional trials are needed.

While the benefit of massage therapy on cancer pain may be mixed, existing trials suggest that massage therapy is safe in patients with cancer. However, certain precautions should be taken when providing massage therapy to patients with cancer:

Avoid directly massaging any open wounds, hematomas, or areas with skin breakdown.

Acupuncture applies needles, heat, pressure, and other treatments to one or more places on the skin known as acupuncture points and is often sought by patients with cancer for the management of pain. (Refer to the PDQ summary on Acupuncture for a comprehensive review of the evidence supporting the role of acupuncture for the management of pain.)

Music Interventions for Pain

Music Therapy and Music Medicine

There are generally two broad categories of music-based interventions referenced within health care research.

Music therapy is the clinical and evidence-based use of active and receptive, tailored, music-based interventions to accomplish individualized goals within a therapeutic relationship, delivered by a credentialed professional (music therapist-board certified, or MT-BC) who has completed an approved program in music therapy.[9]

Music therapists use a variety of music-based interventions that include live, interactive music making or carefully selected recorded music. Some examples include music improvisation, song writing and singing, and music relaxation.

A music therapist chooses interventions on the basis of an assessment of a patient's immediate and long-term needs (e.g., pain management, anxiety reduction, coping strategies, and skills).

Music medicine is the use of passive music listening (usually prerecorded music) for distraction, delivered by a medical professional without specialized music training.[10]

Music therapy and music medicine interventions have been used to relieve acute and chronic pain related to noxious procedures and treatments and the disease process. Music reduces pain via the mutually inhibitory neuroanatomical pathways that are shared between pain and reward processing.[11] Neuroscience studies are consistent in suggesting that pleasant emotional responses to music activate brain structures related to reward, emotion, and attention and decrease activation in areas associated with aversive events.[12,13,14] Music from an individual's personal collection that elicits a positive emotional response has the most robust effect in increasing pain tolerance, decreasing anxiety, and increasing perceived control.[15,16,17]

Meta-analyses summarizing the effect of music on pain indicate small to moderate benefit, with a high level of heterogeneity. There is preliminary evidence that music interventions delivered by music therapists are more effective than music medicine interventions.[10,18]

Studies reporting rates of 50% pain reduction indicate that participants in music listening had a 70% greater probability of experiencing at least a 50% pain reduction than did controls (n = 4 studies).[19] There is also preliminary evidence that music reduces opioid requirements, but the benefits are small and the clinical importance is unclear.[19] Music-based interventions specifically for cancer patients found a moderate pain-reducing effect of a 0.54 standardized unit difference between music and usual-care groups (5 studies, n = 391).[20]

While initial results are promising, the quality of evidence for music and cancer pain studies is low, often because of wide confidence intervals and high variability in study quality.[20] Common sources of bias and low quality include nonblinding of participant and study personnel, lack of theory guiding music selection and delivery, and incomplete reporting of intervention details.[13,21,22]

Characteristics of Music Interventions for Pain

Characteristics of music interventions for pain include the following:

Music interventions can be used as adjuncts to analgesic medications.

When available, live music is preferred, delivered by a board-certified music therapist.

When recorded music is to be used, patients should be encouraged to choose music from their personal collections that is emotionally meaningful to them.

When several pieces of music are to be used, they should be played so that up-tempo and more complex pieces are heard at the beginning, with tempo and overall complexity decreasing from beginning to end.

A general orientation to music listening should be provided to patients and caregivers, to include the operation of any equipment and instructions to patients for when they need additional assistance.

Music listening through headphones may be contraindicated during painful procedures because it prevents patients from hearing instructions or comments from physicians.[23]

Music introduced before a procedure is more effective than music introduced during or after a procedure.[18]

Cognitive-Behavioral Interventions

Cognitive-behavioral interventions are an important part of a multimodal approach to pain management. They help the patient obtain a sense of control and develop coping skills to deal with the disease and its symptoms. Guidelines by a National Institutes of Health assessment panel suggest integration of pharmacologic and behavioral approaches for treatment of pain and insomnia.[24] Other studies suggest that behavioral interventions targeted to specific symptoms, such as pain and fatigue, can significantly reduce symptom burden and improve the quality of life for patients with cancer.[25][Level of evidence: I] Realistic expectations are needed for delivery of cognitive-behavioral interventions. One study [26][Level of evidence: I] of cognitive-behavioral interventions for pain management randomly assigned 57 patients (most of whom were women with metastatic breast cancer who were maintained on daily opioid use for pain) to three 20-minute interventions delivered by audiotape (progressive muscle relaxation [PMR], positive mood induction, or a distraction condition) or to a no-intervention control. The patients were provided the audiotapes by a research nurse, given brief instructions, and asked to use the tapes at least five times a week for 2 weeks; more than half of the patients reported complying with these instructions. The relaxation condition and the "distraction" condition (self-selected informational tapes) produced significant immediate effects on pain, but the positive mood induction tapes showed no effects. The effects, however, neither carried over to general symptom management nor affected pain management at other times. One conclusion of this study is that ideally, interventions should be matched to patient preferences; for more extended effects, additional instruction and support may be needed, as suggested by other studies.

Interventions introduced early in the course of illness are more likely to succeed because they can be learned and practiced by patients while they have sufficient strength and energy. Patients and their families should be given information about and encouraged to try several strategies, and to select one or more of these cognitive-behavioral techniques to use regularly:

Relaxation and Imagery

Simple relaxation techniques (see examples listed below) should be used for episodes of brief pain (e.g., during procedures). Brief, simple techniques are preferred when the patient's ability to concentrate is compromised by severe pain, a high level of anxiety, or fatigue.

Hypnosis

Hypnotic techniques may be used to induce relaxation and may be combined with other cognitive-behavioral strategies.[27][Level of evidence: I] Hypnosis is effective in relieving pain in individuals who can concentrate well, can use imagery, and are motivated to practice. A randomized but unblinded study of preoperative hypnosis in women undergoing excisional breast biopsy or lumpectomy revealed that women who underwent hypnosis required less propofol and lidocaine use during surgery and scored lower on measures of pain, nausea, fatigue, discomfort, and emotional upset at discharge.[28][Level of evidence: I]

Cognitive Distraction and Reframing

Focusing attention on stimuli other than pain or negative emotions accompanying pain may involve distractions that are internal (e.g., counting, praying, or making self-statements such as "I can cope") or external (e.g., listening to music, watching television, talking, listening to someone read, or using a visual focal point). In the related technique, cognitive reappraisal, patients learn to monitor and evaluate negative thoughts and replace them with more positive thoughts and images.

Patient/Family Education

Both oral and written information and instructions should be provided about pain, pain assessment, and the use of drugs and other methods of pain relief.[29,30,31][Level of evidence: I] Patient education should emphasize that almost all pain can be effectively managed. Major barriers to effective pain management (refer to the list of Barriers to Effective Cancer Pain Management in the Overview section of this summary) should be discussed to correct patient and family misconceptions. Health care providers need to take into consideration family members' interpretation of patient pain when providing pain management education services, as some caregivers overestimate patient pain.[32][Level of evidence: II] Educational intervention programs to help patients who have cancer and their families manage pain have been described and may improve clinical outcomes.[33][Level of evidence: II] These programs are based on adult learning principles and incorporate key strategies, including provision of information using academic detailing, skill building with ongoing nurse-coaching, and interactive nursing support.[34][Level of evidence: IV];[35][Level of evidence: I] Training partners to participate in management of cancer pain increases partner self-efficacy for controlling their loved one's pain and other symptoms.[36][Level of evidence: II]

Psychotherapy and Structured Support

Some patients benefit from short-term psychotherapy provided by trained professionals. Patients whose pain is particularly difficult to manage and who develop symptoms of clinical depression or adjustment disorder should be referred to a psychiatrist or psychologist for diagnosis. The relationship between poorly controlled pain, depression, and thoughts of suicide should not be ignored.

Support Groups and Pastoral Counseling

Because many patients benefit from peer support groups, clinicians should be aware of locally active groups and offer this information to patients and their families. Pastoral counseling members of the health care team should participate in meetings to discuss patients' needs and treatment. They should also be a source of information on community resources for spiritual care and social support.

As you breathe out slowly, feel yourself beginning to relax; feel the tension leaving your body.

3.

Now breathe in and out slowly and regularly, at whatever rate is comfortable for you. Let the breath come all the way down to your stomach, as it completely relaxes.

4.

To help you focus on your breathing and breathe slowly and rhythmically: (a) breathe in as you say silently to yourself, "in, two, three"; (b) breathe out as you say silently to yourself, "out, two, three." Or, each time you breathe out, say silently to yourself a word such as "peace" or "relax."

5.

Do steps 1 through 4 only once or repeat steps 3 and 4 for up to 20 minutes.

6.

End with a slow deep breath. As you breathe out say to yourself, "I feel alert and relaxed."

Exercise 2. Simple Touch, Massage, or Warmth for Relaxation

1.

Touch and massage are age-old methods of helping others relax. Examples include the following:

Warm foot soak in a basin of warm water, or wrap the feet in a warm, wet towel.

Massage (3–10 minutes) may consist of whole body or be restricted to back, feet, or hands. If the patient is modest or cannot move or turn easily in bed, consider massage of the hands and feet.

2.

Use a warm lubricant (e.g., a small bowl of hand lotion may be warmed in the microwave oven, or a bottle of lotion may be warmed by placing it in a sink of hot water for about 10 minutes).

3.

Massage for relaxation is usually done with smooth, long, slow strokes. (Rapid strokes, circular movements, and squeezing of tissues tend to stimulate circulation and increase arousal.) However, try several degrees of pressure along with different types of massage (e.g., kneading and stroking). Determine which is preferred.

4.

Especially for the older person, a back rub that effectively produces relaxation may consist of no more than 3 minutes of slow, rhythmic stroking (about 60 strokes per minute) on both sides of the spinous process from the crown of the head to the lower back. Continuous hand contact is maintained by starting one hand down the back as the other hand stops at the lower back and is raised. Set aside a regular time for the massage. This gives the patient something to look forward to and depend on.

Exercise 3. Peaceful Past Experiences

Something may have happened to you a while ago that brought you peace and comfort. You may be able to draw on that past experience to bring you peace or comfort now. Think about these questions:

1.

Can you remember any situation, even when you were a child, when you felt calm, peaceful, secure, hopeful, or comfortable?

2.

Have you ever daydreamed about something peaceful? What were you thinking of?

3.

Do you get a dreamy feeling when you listen to music? Do you have any favorite music?

4.

Do you have any favorite poetry that you find uplifting or reassuring?

5.

Have you ever been religiously active? Do you have favorite readings, hymns, or prayers? Even if you haven't heard or thought of them for many years, childhood religious experiences may still be very soothing.

Additional points: Some of the things you think of in answer to these questions, such as your favorite music or a prayer, can probably be recorded for you. Then you can listen to the tape whenever you wish. If your memory is strong, you may simply be able to close your eyes and recall the events or words.

Exercise 4. Active Listening to Recorded Music

1.

Obtain the following:

A cassette player or tape recorder. (Small battery-operated machines are more convenient.)

Earphones or a headset. (This is a more compelling stimulus than a speaker a few feet away, and it avoids disturbing others.)

Cassette recording of music you like. (Most people prefer fast, lively music, but some people select relaxing music. Other options are comedy routines, sporting events, old radio shows, or stories.)

2.

Mark time to the music, e.g., tap out the rhythm with your finger or nod your head. This helps you concentrate on the music rather than your discomfort.

3.

Keep your eyes open and focus steadily on one stationary spot or object. If you wish to close your eyes, picture something about the music.

4.

Listen to the music at a comfortable volume. If the discomfort increases, try increasing the volume; decrease the volume when the discomfort decreases.

5.

If these steps are not effective enough, try adding or changing one or more of the following: massage your body in rhythm to the music; try other music; mark time to the music in more than one manner (e.g., tap your foot and finger at the same time).

Additional points: Many patients have found this technique to be helpful. It tends to be very popular, probably because the equipment is usually readily available and is a part of daily life. Other advantages are that it is easy to learn and is not physically or mentally demanding. If you are very tired, you may simply listen to the music and omit marking time or focusing on a spot.

Integration of behavioral and relaxation approaches into the treatment of chronic pain and insomnia. NIH Technology Assessment Panel on Integration of Behavioral and Relaxation Approaches into the Treatment of Chronic Pain and Insomnia. JAMA 276 (4): 313-8, 1996 Jul 24-31.

Discharge Planning

Patients and families may have difficulty remembering details of the pain management plan and should be given a written pain-management plan. The patient and family should receive clear instructions regarding telephone contact for more urgent questions relating to pain management.

Treating Elderly Patients

Like other adults, older patients require comprehensive assessment and aggressive management of cancer pain. Older patients are at risk for undertreatment of pain, however, because of underestimation of their sensitivity to pain, the expectation that they tolerate pain well, and misconceptions about their ability to benefit from the use of opioids. Issues in assessing and treating cancer pain in older patients include:

Multiple chronic diseases and sources of pain.

Age and complex medication regimens place them at increased risk for drug-drug and drug-disease interactions.

Visual, hearing, motor, and cognitive impairments.

The use of simple descriptive, numeric, and visual-analog pain-assessment instruments may be impeded. Cognitively impaired patients may require simpler scales and more frequent pain assessment.

Nonsteroidal anti-inflammatory drug (NSAID) side effects.

Although effective alone or as adjuncts to opioids, NSAIDs are more likely to cause gastric and renal toxicity and other drug reactions such as cognitive impairment, constipation, and headaches in older patients. Alternative NSAIDs (e.g., choline magnesium trisalicylate) or coadministration of misoprostol with NSAIDs should be considered to reduce gastric toxicity.

Opioid effectiveness.

Older persons tend to be more sensitive to the analgesic and central nervous system depressant effects of opioids. Peak opioid effects are generally greater and the duration of pain relief may be longer.

Although useful for patients who have nausea or vomiting, the rectal route may be inappropriate for elderly or infirm patients who are physically unable to place the suppository in the rectum.

Postoperative pain control.

Following surgery, surgeons and other health care team members should maintain frequent direct contact with the elderly patient to reassess the quality of pain management.

Change of setting.

Reassessment of pain management and appropriate changes should be made whenever the elderly patient moves (e.g., from hospital to home or nursing home).

Changes to This Summary (01 / 30 / 2014)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

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About This PDQ Summary

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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of pain. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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